This study, examining the longitudinal relation among physical activity, body mass index, and development of type 2 diabetes in a high-risk population, is unique because diabetes was determined by oral glucose tolerance testing rather than by self-report. A physical activity questionnaire assessing past year leisure and occupational activity was administered to 1,728 nondiabetic Pima individuals aged 15-59 years as part of a series of clinic examinations in the Gila River Indian Community from 1987 to 2000. During an average follow-up period of 6 years, 346 subjects developed diabetes. Using time-dependent Cox proportional hazards modeling adjusting for age, the authors found that total activity was related to diabetes incidence in women and men (p < 0.05 in women only). After additional adjustment for body mass index, the relation between activity and diabetes incidence was weakened in both men and women. When the age-adjusted diabetes incidence rates were examined by levels of activity stratified by tertile of body mass index, the diabetes incidence rate remained lower in more active than in less active men and women from all body mass index groups, with the exception of the middle body mass index tertile in men (p < 0.05 in women only). These results suggest that the adoption and maintenance of a physically active lifestyle can play a significant role in preventing type 2 diabetes.