Lipopolysaccharide (LPS) and homologous cytokines were tested for their effect on core temperature in mice using battery-operated telemetric devices placed in the peritoneal cavity. One microgram LPS injected intraperitoneally (i.p.) induced a biphasic effect on core body temperature (Tc), a rapid decrease in Tc with a peak around 30–45 min followed by a prolonged rise around 150–300 min. When a higher dose of LPS (5 jxg) was used, the hypothermia was increased in magnitude and lasted much longer, and no fever was observed. Both the decrease and the increase in Tc caused by LPS were prevented by pretreating the mice with indomethacin, a cyclooxygenase inhibitor, but not by a nitric oxide synthase inhibitor. Mouse interleukin-1β (mIL-1β, 100 ng, i.p.) induced changes resembling those to LPS, a short-lived decrease in Tc, followed by a small increase. When 1 μg mIL-1β was injected a profound hypothermia lasting more than 3 h was observed. Mouse IL-6 (1 μg) failed to alter core temperature after either intravenous (i.v.) or i.p. administration. Human IL-6 was also ineffective. Recombinant mouse tumor necrosis factor-α (mTNFα) also failed to alter the core temperature of mice when injected at a dose of 1 μg (i.p. or i.v.). However, a higher dose of mTNFα (5 μg i.p.) caused a short-lived decrease in Tc, followed by a small increase. Similar results were obtained with LPS and the cytokines in C57B1/6J mice, except that mIL-1β was ineffective in this strain. These results indicate that the endocrine, neurochemical and behavioral responses to IL-1, IL-6 and TNFα administration cannot be explained by changes in Tc, although they may contribute to them. They also suggest that IL-1β may account for the fever observed following LPS, but that these cytokines are probably not the only factors involved in LPS-induced changes in Tc.