The incidence of lower-extremity amputations was estimated in the Pima Indians of the Gila River Indian Community in Arizona, a population with a high prevalence of non-insulin-dependent diabetes mellitus (NIDDM). Between 1972 and 1984, from a study population of 4399 subjects, lower-extremity amputations were performed on 84 patients, 80 (95%) of whom had NIDDM. Among diabetic subjects, the incidence rate of first lower-extremity amputations was higher in men than in women. Rates increased significantly with increasing duration of diabetes. Presence of medial arterial calcification, retinopathy, or nephropathy; absence of patellar tendon reflexes; impaired great toe vibration-perception threshold; and degree of fasting and 2-h postload hyperglycemia were significant risk factors for amputations. Serum cholesterol concentration, blood pressure, age, and absence of Achilles tendon reflexes were not predictive of amputations. The death rate was greater in diabetic amputees than in diabetic nonamputees of similar age, sex, and duration of diabetes, and a significant increase in cardiovascular deaths was observed in diabetic subjects with amputations. The incidence rate of lowerextremity amputations in diabetic Pima Indians is higher than that reported in other diabetic populations. This may reflect differences in risk or a more complete case ascertainment than was possible in previous studies. If the latter is true, the rate of amputations in diabetic individuals may be higher than has been previously appreciated.