Physical activity has been recommended by physicians in managing patients with noninsulin-dependent diabetes mellitus (NIDDM); however, it is unclear whether physical activity can prevent this disease. Several prospective studies have suggested that increased physical activity may lead to the prevention of NIDDM. In the University of Pennsylvania Alumni Health Study, 5990 men were surveyed to determine the relationship between physical activity and the development of NIDDM. A total of 202 men developed NIDDM from 1962 to 1976. Leisure-time physical activity, expressed in kilocalories (kcal) was inversely related to the development of NIDDM. Incidence rates declined as energy expenditure increased. For each 2000-kcal increment in energy expenditure, the risk of NIDDM was reduced by 24% [relative risk (RR) 0.76, 95% confidence interval (CI) 0.63–0.92]. This association remained when adjusting for obesity, hypertension, and parental history of diabetes. The protective effect of physical activity was strongest in individuals at highest risk for NIDDM. Based on the review of data from several large prospective studies, it is quite likely that increased levels of physical activity are effective in preventing NIDDM, and the protective benefit is especially pronounced in those individuals who have the highest risk of disease.