This study investigated the roles of endotoxemia and heat-induced tissue damage in the pathology of heat stroke. In groups of eight, male Wistar rats were treated with heat exposure only (HE), or heat exposure with turpentine (T+HE), dexamethasone (D+HE) and turpentine and dexamethasone combined (TD+HE). The rats remained sedated for 2 h after receiving the respective treatments, followed by heat exposure until the core temperature (Tc) was 42 °C for 15 min; control rats received turpentine (T), dexamethasone (D) and turpentine and dexamethasone (TD) without heat stress. Blood samples were collected before treatment (Baseline I), after 2 h of passive rest (Baseline II), at Tc 40 °C (T40) and 15 min after achieving Tc 42 °C. No rats died in the non-heat-stressed groups. Survival rate was lowest in the TD+HE rats (37.5%), followed by the HE (62.5%), T+HE (75%) and D+HE (100%) rats (P < 0.05). The mean (SD) duration of survival at Tc 42 °C was shortest in the TD+HE rats (9.9 ± 6.2 min) (P < 0.01), followed by the T+HE (11.3 ± 6.1 min) and the HE (12.2 ± 4 min) (P < 0.05) rats. The increase in plasma IL-6 concentrations was highest in the T+HE (352%) and HE (178%) rats (P < 0.05). D+HE treatment suppressed the increases in aspartate transaminase, alanine aminotransferase, and plasma IL-6 and LPS concentrations during severe heat stress. Heat stroke can be triggered by endotoxemia or heat-induced tissue damage and pre-existing inflammation compromises heat tolerance, whereas blocking endotoxemia increases heat tolerance.