Fenfluramine has been demonstrated to have a biphasic effect on glucose removal by skeletal muscle during forearm perfusion. A prompt early increase in glucose removal by skeletal muscle, lasting 90 to 120 minutes, disappeared with the release of free fatty acids. The metabolic effect of fenfluramine on glucose removal occurred without increase in lactate release, suggesting complete oxidation of glucose by skeletal muscle. The effect of fenfluramine on blood glucose was assessed in maturity onset and insulin-requiring diabetics. The drug was most suitable as a hypoglycemic agent when administered immediately before a meal in order that the maximum hypoglycemic action occurred during the period of post-absorption hyperglycemia. When administered before a meal fenfluramine consistently lowered blood glucose levels in maturity onset diabetes mellitus for at least two hours. A similar but less marked action was seen in insulin-requiring diabetics. Blood glucose levels were lowered by fenfluramine in diabetics who were maintained on diet alone or diet plus tolbutamide without the risk of lactic acidosis and without any direct effect on insulin secretion.