Oseltamivir phosphate (Tamiflu), an anti-influenza virus drug, is hydrolyzed by carboxylesterase to an active metabolite. The metabolite inhibits the influenza virus-specific neuraminidase. In this study, the effects of oseltamivir on normal core body temperature were studied in mice. Oseltamivir (30-300 mg/kg, intraperitoneally (i.p.) and 100-1000 mg/kg, orally (p.o.)) dose-dependently lowered the body temperature. The effects of oseltamivir (p.o.) continued longer than those of oseltamivir (i.p.), and approximately triple doses of oral oseltamivir were needed to produce the same peak effects as intraperitoneal oseltamivir. The non-steroidal anti-inflammatory drug diclofenac (1-30 mg/kg, i.p.) did not affect body temperature, and (at 30 and 60 mg/kg, s.c.) did not interact with the hypothermic effects of oseltamivir (100 mg/kg, i.p.). Zanamivir, which also inhibits neuraminidase, did not produce hypothermia at doses of 100 and 300 mg/kg, i.p. Clopidogrel (100, 300 mg/kg, i.p.), which is metabolized by the same carboxylesterase, tended to decrease the hypothermic effects of oseltamivir (100 mg/kg, i.p.). These results suggest that the hypothermic effects of oseltamivir are due to its hydrolytic metabolite, and that the hypothermia observed in mice has some relationship to the antipyretic effects and severe hypothermia (adverse event) observed in influenza patients after taking oseltamivir.