As CNS residents, mast cells contain many cytokines and are localized primarily near large blood vessels in the diencephalon and within the leptomeniges, making them candidates for immune to neural 'cross-talk'. Using mast cell deficient Kit^W-sh/W-sh mice, we assessed the role of these cells in the thermoregulatory component of the immune response to lipopolysaccharide. Kit^W-sh/W-sh and wild type (WT) mice differ in several respects in response to injection of a high dose of LPS (1 mg/kg i.p.). Core temperature (Tc) of WT mice decreases by ~3°C, while Kit^W-sh/W-sh mice do not become hypothermic but instead exhibit pronounced low frequency Tc oscillations around their baseline temperature. Additionally, Kit^W-sh/W-sh mice have lower levels of whole brain TNF-, but no differences in IL-1, IL-6, INF- or histamine, compared to WT mice following injection of the high dose of LPS, consistent with the role of TNF- in sepsis. Kit^W-sh/W-sh mice have increased resistance to LPS, and some survive a dose of LPS that is lethal in littermate controls. In contrast, Kit^W-sh/W-sh and WT mice are similar in other aspects, namely in the hyperthermia following injection of TNF- (1.5µg i.c.v.), reduced night time Tc and locomotor activity (to 1mg/kg LPS), response to a low-dose of LPS (10 µg/kg, i.p.) and response to subcutaneous turpentine injection. These results indicate that mast cells play a role in the regulation of thermoregulatory responses and survival following sepsis induction and suggest a brain site of action.