Cancer is a leading cause of morbidity and mortality in the United States and other developed countries. In searching for preventive strategies against this disease, researchers have postulated that antioxidant vitamins may play a role in preventing cancer since several plausible biological mechanisms exist. This article reviews the epidemiological evidence for a role of antioxidant vitamins (in particular, beta-carotene, vitamin E, and vitamin C) in the development of cancer. Observational studies provide fairly consistent data for an inverse association between high intake of antioxidant vitamins, especially beta-carotene and vitamin C, and cancer risk. However, randomized trials generally have not supported the hypothesis. Several explanations for these inconsistent findings are possible. These include: 1) confounding by other healthy dietary and nondietary habits in observational studies; 2) the protective role of a combination of many different nutrients present in fruits and vegetables, rather than the single nutrient or combination of two nutrients that most trials have tested; 3) inadequate duration of follow-up in most randomized trials; and 4) heterogeneity of the populations studied. Reliable epidemiological evidence regarding whether antioxidant vitamins play a role in preventing cancer will have to come from both observational studies and randomized trials since these different study designs each have unique strengths and limitations. Based on the available evidence, it seems prudent to advocate a diet rich in fruits and vegetables, rather than the consumption of specific antioxidant vitamin supplements, in order to decrease the risk of developing cancer.