This study was designed to evaluate the influence of intravenous infusion (72 mg min-1) of lysine acetylsalicylate (LAS), an inhibitor of endogenous prostaglandin synthesis, on glucose homeostasis in normal man. LAS infusion produced a transient decrease of both hepatic glucose production (Ra, p less than 0.01) and peripheral glucose uptake (Rd, p less than 0.01). Since Ra fell more than Rd, a slight but significant decrease of plasma glucose concentration occurred. Glucose metabolic clearance rate also showed a rapid, although transient, decrease after the start of LAS infusion. Plasma insulin rose twofold in response to LAS, while plasma glucagon remained unchanged. The failure of the glucose clearance to increase as a consequence of the augmented insulin levels suggests that salicylate compounds may cause a state of insulin resistance.