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alpha-Melanocyte-stimulating hormone (alpha-MSH) or paracetamol was injected into a lateral cerebral ventricle (I.C.V.) of rabbits with elevations in rectal temperature induced by sodium arachidonate (I.C.V.), prostaglandin E2 (I.C.V.) or leucocytic pyrogen (I.V.). alpha-MSH (200 ng) was more effective than paracetamol (0.5 mg) in reducing fever caused by leucocytic pyrogen, but it did not alter hyperthermia induced by sodium arachidonate. In contrast, paracetamol reduced hyperthermic responses to arachidonate by about 70%. Neither alpha-MSH nor paracetamol affected hyperthermic responses to prostaglandin E2. The doses of alpha-MSH and paracetamol used in these experiments did not interfere with thermoregulation in a cold environment (10 degrees C). We conclude (1) that alpha-MSH and paracetamol differ in their central mechanism of antipyresis or (2) that inhibition of arachidonic acid metabolism by paracetamol is not requisite for its antipyretic effect, in which case central release of alpha-MSH may mediate the antipyretic effect of paracetamol.