Insulin binding was studied on circulating erythrocytes isolated from 12 normal and 12 untreated, adult, nonobese, nonketotic, non-insulin-dependent diabetic subjects. Insulin binding in normal subjects was higher than in diabetics (P less than 0.01); binding variation was caused mainly by a reduction in insulin receptor concentration. Insulin binding was inversely correlated with fasting serum insulin levels (R = 0.49; P less than 0.01). The close agreement between the present data and previous data on other cell populations suggests that isolated erythrocytes may be a useful tool in clinical investigations on the human insulin receptor.