In 1928, while Szent-Györgyi was still at Cambridge, the Hungarian minister of education, Count Kuno Klebelsberg, invited him to return to Hungary to chair the medical chemistry department at the University of Szeged. Klebelsberg wanted to rebuild Hungarian scientific institutions, and had obtained Rockefeller Foundation (RF) support for expanding the programs at Szeged. Though Szent-Györgyi loved Cambridge, there was little chance of advancement there, so he accepted the offer, taking up his new position in January 1931.

Szent-Györgyi's new responsibilities included teaching and administration as well as research. He soon established a reputation for fascinating lectures and an informal leadership style. More traditional faculty were sometimes startled or affronted by Szent-Györgyi's behavior: dining or playing sports with his students, riding his bicycle to visit colleagues (as was common at Cambridge)--but the students loved him for his free and spontaneous approach to education.

After only six months Szent-Györgyi had established a small but important research center with over a dozen different projects in progress. Within a year he had initiated Hungary's first degree program in biochemistry (which he distinguished from the "medical chemistry" taught in medical schools), and had eight RF fellows on his faculty. He was also chairman of the Natural Science Research Council in Szeged, which administered the $200,000 RF grant. His dealings with the RF during the next several years set what became a lifelong pattern with regard to funding agencies: initial enthusiasm, followed by frustration and disillusionment (on both sides) as Szent-Györgyi made extravagant claims and requested additional funds, but balked at justifying the expenses with detailed research plans and budgets.

In the fall of 1931, an American post-doctoral fellow, Joseph Svirbely, joined Szent-Györgyi's research team. Svirbely had been working with C. G. King at the University of Pittsburgh, trying to isolate vitamin C. Szent-Györgyi gave him the remains of the hexuronic acid he had isolated at the Mayo Clinic and asked him to test it, using guinea pigs with induced scurvy. Repeated trials proved that "hexuronic acid" was, in fact, vitamin C. (Szent-Györgyi had suspected this, but had put the project aside rather than take up the messy, expensive, and labor intensive animal studies required.) King, meanwhile, had also been close to reaching a similar conclusion. Svirbely wrote to his former mentor in March 1932, telling King what he had found at the Szeged laboratory, adding that he and Szent-Györgyi were submitting a report to Nature. On April 1, 1932, Science published King's announcement that he had discovered vitamin C, which was identical to hexuronic acid. King cited Szent-Györgyi's earlier work on hexuronic acid but gave him no credit for vitamin C. The discovery story was picked up quickly by the American press. Astonished and dismayed, Szent-Györgyi and Svirbely sent off their own report to Nature, challenging King's priority in the discovery. A bitter controversy ensued. King, as was well-known, had been working on the problem for over five years; he had many supporters, who were ready to vilify Szent-Györgyi as a plagiarist. Yet European and British scientists also knew of Szent-Györgyi's long history with this anti-oxidant substance and accepted his claim.

Apart from the question of priority, Szent-Györgyi had a more immediate problem: he could not repeat the experiments with vitamin C because he had used up the last of his supply. He had no large supply of adrenal glands on hand from which to extract more, and attempts with various fruits and vegetables failed as well. In the fall of 1932 it occurred to him to test paprika peppers for vitamin C content. Paprika proved to be a very rich source of vitamin C, and supply was no problem--Szeged was the paprika capital of Hungary. Szent-Györgyi immediately mobilized his staff for the large-scale extraction of vitamin C from peppers. Within a week, they had produced over three pounds of the pure crystalline substance. Rather than patent the process or the product, Szent-Györgyi sent batches to all researchers working on vitamin C or related problems (including Norman Haworth at Birmingham, who established its chemical nature, and then, with Szent-Györgyi, re-named it "a-scorbic" acid, since it prevented scorbutus, i.e., scurvy). Szent-Györgyi also sent a supply to the Health Organization of the League of Nations, to distribute in areas where scurvy was still prevalent (e.g., Norway).

Szent-Györgyi spent the next several years "preaching vitamin C" (as he put it) all over Europe, suggesting that it might be valuable as a preventive or cure for the common cold and other illnesses. He attempted to interest some of the British biochemists in running some clinical trials, but they considered the idea crankish and refused to consider it. Vitamin C proved disappointing as a miracle cure, however, and Szent-Györgyi eventually got back to his basic research in other areas.

In the meantime, building on his earlier work in the biochemistry of plant respiration, Szent-Györgyi had begun to investigate respiration in muscle tissue, using minced pigeon breast muscle. Pigeon breast was an ideal material, a powerful muscle that burned energy at a high rate to sustain flight, and also readily available. It was already known that fumaric, malic, and succinic acids (collectively called dicarboxylic acids) played some role in respiration, but scientists assumed that they were consumed in the process. When Szent-Györgyi added small amounts of these to his minced pigeon muscle, he found that far more oxygen was consumed than would be needed to oxidize them. The acids were not consumed as fuels, he realized, but served as catalysts, i.e., they maintained the combustion reaction without being changed themselves. Each of them stimulated the oxidation of a carbohydrate present in the tissue cells. This was an important new idea. Szent-Györgyi proposed that the hydrogen from a substance in the cell (e.g., a carbohydrate) reduced a first dicarboxylic acid, the oxaloacetic acid; the resulting malic acid reduced fumaric acid; the succinic acid thus produced in turn transferred its hydrogen to cytochromes. By 1937, Szent-Györgyi had identified the process as a cycle and was close to elaborating all of the steps that generate adenosine triphosphate (ATP), the energy-carrying molecule in all living cells. As it turned out, Szent-Györgyi's focus on malate and oxaloacetate was an error, and Hans Krebs soon found that the key link was citric acid. Thus "Szent-Györgyi's cycle" became the citric acid cycle or Krebs cycle; Krebs, who won a Nobel prize in 1953 for the work, later called it the tricarboxylic acid cycle.

Szent-Györgyi was quite surprised when, in October 1937, he was informed by the Royal Karolinska Institute in Stockholm that he had been awarded the Nobel Prize for Physiology or Medicine, "for his discoveries in connection with the biological combustion processes, with especial reference to vitamin C and the catalysis of fumaric acid." (Norman Haworth and another vitamin researcher Paul Karrer, shared that year's prize in chemistry, also in part for work on vitamin C.) The Nobel prize made Szent-Györgyi a national hero in Hungary; he was only the fourth Hungarian Nobel laureate, and the first to win it while actually residing there.

Szent-Györgyi's research into muscle tissue respiration led him to the question of how muscle moves. Russian researchers had reported in 1939 that the muscle protein myosin could interact with and split ATP. Though discovered in 1929, ATP had not yet been identified as the principal source of energy in cells (it releases tremendous energy when its phosphate bonds are split). Szent-Györgyi reasoned that the myosin-ATP interaction might well explain the movement of muscle. To learn more about how muscle tissue changes its shape and size, and about the chemical substances involved, he extracted myosin from rabbit muscle, drew it into a hypodermic syringe, then pressed it out into fine threads. When he added ATP, the threads rapidly contracted to one-third their original size, just like a muscle fiber tensing. "To see myosin contract and see one of the oldest and most mysterious signs of life--motion--reproduced the first time in vitro. . . was the most exciting experience of my research career," he commented later. He and his research team, notably Bruno Straub and Ilona Banga, went on to discover that muscle tissue contained a second protein, actin, which combined with myosin to form interlocking fibers; the higher the percentage of actin, the stronger the fiber's contraction response to ATP. By 1944, the team had elucidated the mechanism of muscle contraction and clarified the role of ATP in the process. They published a series of papers, Studies on Muscle from the Institute of Medical Chemistry which reported on their five years of research.

In 1944, however, Szent-Györgyi had more serious problems. Never a supporter of fascist policies, he had helped Jewish colleagues (including Hans Krebs) during the 1930s, and had strongly resisted the growing campus anti-Semitism and militancy, even facing down angry groups of students at times. Hungary was loosely allied with the Axis powers after 1938, but by 1942 many intellectuals (including Szent-Györgyi) and some politicians were publicly protesting this alliance and working quietly to undermine the Nazis. In 1943 the Hungarian prime minister asked Szent-Györgyi to open secret negotiations with the Allies. Szent-Györgyi traveled to Istanbul (allegedly to give a scientific lecture) and made contact with Allied agents there, but German agents learned of the plan. By the summer of 1944, at Hitler's request, Szent-Györgyi was under house arrest. He slipped away after several months, and spent the remainder of the war hiding from the Nazis in Szeged and Budapest.