The organophosphate pesticide (OP) chlorpyrifos leads to an acute period of hypothermia followed by a delayed fever in the rat. Methyl scopolamine, a peripheral muscarinic antagonist, is thought to have little effect on body temperature of the rat because it does not cross the blood brain barrier. However, administration of methyl scopolamine (1 mg/kg, i.p.) during the period of chlorpyrifos-induced fever results in a rapid recovery of core temperature. This indicates a peripheral cholinergic pathway is operative in the febrile response to chlorpyrifos and possibly other modes of fever. In this study, we evaluated the possible antipyretic role of methyl scopolamine (i.p.) to a variety of stimuli that lead to fever-like responses in the rat: stress-induced (handling and cage switch), chlorpyrifos-induced (15 mg/kg, p.o.), nocturnal-induced, and lipopolysaccharide (LPS)-induced fever (50 microg/kg, i.p.). Methyl scopolamine led to marked reversal in the elevated core temperature caused by handling, cage switch, and during the nocturnal phase. It is of interest to note that all these elevations of core body temperature are prostaglandin mediated and are blocked with the antipyretic drug, sodium salicylate. However, LPS-induced fever, also a prostaglandin dependent fever, was unaffected by methyl scopolamine. Methyl scopolamine also lowered baseline core temperature when administered during the afternoon, but not during the morning in unstressed animals. It is proposed that a peripheral cholinergic pathway, possibly mediated through afferent vagal pathways, is operative in controlling core temperature during fevers associated with stress, nocturnal phase, and a pesticide. During recovery from exposure to a LPS, the fever appears to be mediated independently of peripheral cholinergic activation.