The mechanism of the antipyretic effect of indomethacin (IM) on fever induced by bacterial pyrogen (LPS, 0.2 microgram/kg, i.v.), leukocytic pyrogen (LP, 2 ml/kg, i.v.) and 2,4-dinitrophenol (DNP, 20 mg/kg, i.m.) in male adult rabbits was studied. In plasma, the biological half lives of IM in normal and LPS-injected rabbits were estimated to be 24 and 21 min in the early phase and 72 and 51 min in the late phase, respectively. A potent antipyretic effect was observed with intravenous injection of IM in LPS- and LP-induced fevers, but not in DNP-induced fever. The antipyretic effect was also observed with intracisternal injection of indomethacin at doses of 0.025 and 0.013 mg/kg. The activity of endogenous pyrogen in serum after LPS injection was not suppressed by the injection of IM (10 mg/kg, i.v.). The production of LP by leukocytes in vitro was not inhibited by IM (10 micrograms/ml). In our previous report, it was ascertained that the rectal temperature of normal rabbits remained unchanged after intravenous injection of IM. These results suggest that indomethacin may inhibit only the pyretic processes in the central nervous system.