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1. Several possible mechanisms of the antipyretic action of indomethacin administered cat. 2. Indomethacin did not decrease bacterial endotoxin-induced release of endogenous pyrogen in vivo. 3. Indomethacin (5-40 mug/kg) inhibited the pyrogenic effect of peripherally or centrally administered leucocytic progen. A dose of 10 mug/kg caused a parallel shift to the right of the log dose-response curve for I.V. leucocytic pyrogen and reduced the potency of the pyrogen at least 50%. 4. Incubation of leucocytic pyrogen with indomethacin did not alter its pyrogenic potency. 5. Indomethacin exerted only a slight non-dose-related hypothermic effect in afebrile animals. 6. Indomethacin (up to 1 mg/kg) did not diminish the hyperthermic response to intraventricular administration of prostaglandin E1. 7. This pattern of activity indicates that indomethacin acts centrally to inhibit an effect of leucocytic pyrogen.