With the aim of studying the mechanism by which peripherally injected interleukin-1 increases the serum levels of insulin in conscious rats, the effects of indomethacin, a cyclooxygenase inhibitor, on interleukin-1-induced hyperinsulinemia were examined using male Wistar rats implanted with intra-atrial cannulas. The i.v. injection of interleukin-1 (1 microgram/rat) into conscious rats resulted in a significant increase in serum insulin levels with the peak response being observed 10 min after injection. It was also found that this insulin response to interleukin-1 was dose-related. Pretreatment with indomethacin (3 mg/kg body weight), however, completely blocked the interleukin-1-induced stimulation of insulin secretion. These findings suggest that i.v. injected interleukin-1 stimulates insulin release from the endocrine pancreas by a mechanism involving the prostaglandin system.