Oral administration of a single dose of the anorectic agent mazindol to obese subjects led to a significant improvement in oral glucose tolerance and a concomitant reduction in insulin secretion, but had no effect on the blood glucose and plasma insulin responses to glucose given intravenously. Mazindol, when given to obese subjects in conjunction with a hypocaloric diet, was associated with progressive weight loss and reduction in the fasting levels of blood glucose, plasma insulin, serum triglyceride, and serum cholesterol. When oral glucose tolerance was retested after 16-20 wk, blood glucose and plasma insulin responses were significantly decreased compared with initial control values. It is concluded that one effect of mazindol, when given acutely, is to impair absorption of glucose from the gut. Changes in carbohydrate metabolism after chronic administration of mazindol are entirely consistent with weight loss, although a separate effect of the drug cannot be excluded.