The effect of aspirin on glucose and insulin metabolism was examined with the hyperglycemic clamp technique in 8 normal volunteers. When the plasma glucose concentration was acutely raised and maintained at 125 mg/dl above the basal level after treatment with aspirin (3 g daily for 3 days), acute (0–10 min) and sustained (20–120 min) insulin release were 70% and 45% greater than before treatment. Despite the increased plasma insulin level, the glucose infusion rate remained unchanged (8 ± 0.9 to 9.1 ± 1.2 mg/kgmin). Consequently, the ratio of the glucose infusion rate to the plasma insulin level, an index of tissue sensitivity to endogenous insulin, decreased by 30%, indicative of impaired insulin action. Aspirin did not alter fasting levels of FFA. When ibuprofen, another prostaglandin synthesis inhibitor, was given to 10 normal volunteers, only an effect on acute insulin release could be demonstrated. These results demonstrate that aspirin not only enhances β-cell sensitivity to glucose, but also impairs glucose metabolism in insulin-sensitive tissues. It is not clear whether these effects are related to aspirin’s ability to inhibit prostaglandin synthesis.