Elevated circulating cytokines are observed in heat stroke patients, suggesting a role for these substances in the pathophysiologic responses of this syndrome. Typically, cytokines are determined at end-stage heat stroke such that changes throughout progression of the syndrome are poorly understood. We hypothesized that the cytokine milieu changes during heat stroke progression, correlating with thermoregulatory, hemodynamic and tissue injury responses to heat exposure in the mouse. We determined plasma interleukin (IL)-1, IL-1, IL-2, IL-4, IL-6, IL-10, IL-12p40, IL-12p70, interferon (IFN),macrophage inflammatory protein (MIP)-1, tumor necrosis factor (TNF), corticosterone, glucose, hematocrit and tissue injury during 24h of recovery. Mice were exposed to ambient temperature (T_a) of 39.5±0.2°C, without food and water, until maximum core temperature (T_c,Max) of 42.7°C was attained. During recovery, mice displayed hypothermia (29.3±0.4°C) and a fever-like elevation at 24h (control=36.2±0.3°C vs. heat stressed=37.8±0.3°C). Dehydration (~10%) and hypoglycemia (~65-75% reduction) occurred from T_c,Max to hypothermia. IL-1, IL-2, IL-4, IL-12p70, IFN, TNF and MIP-1 were undetectable. IL-12p40 was elevated at T_c,Max whereas IL-1, IL-6 and IL-10 inversely correlated with T_c, showing maximum production at hypothermia. IL-6 was elevated, whereas IL-12p40 levels were decreased below baseline at 24h. Corticosterone positively correlated with IL-6, increasing from T_c,Max to hypothermia, with recovery to baseline by 24h. Tissue lesions were observed in duodenum, spleen and kidney at T_c,Max, hypothermia and 24h, respectively. These data suggest that the cytokine milieu changes during heat strain recovery with similarities between findings in mice and those described for human heat stroke, supporting the application of our model to the study of cytokine responses in vivo.