A total of 171 untrained, unacclimatized, and unanesthetized rats were used to evaluate the effects of sedentary and work-induced hyperthermia on the incidence of mortality and cellular injury, 24 h postexposure. Cellular injury was defined as serum transaminase activity (SGPT and SGOT) exceeding 1,000 IU/l (heatstroke levels). Both the percent mortality and the percentage of 24-h survivors with transaminase levels above 1,000 IU/l were plotted against maximum core temperatures. Exertion-induced hyperthermia produced a significantly higher incidence of cellular injury and heatstroke death at lower core temperatures than hyperthermia alone. With hyperthermia only, the SGPT and SGOT dose-response curves were identical. When work was combined with hyperthermia, there was a greater incidence of elevated SGOT at lower core temperatures. These curves bore a striking resemblance to curves reflecting heat- and/or work-induced mortality in humans. The results suggest a direct role of physical effort in causing heatstroke injury and mortality.