Thermal tolerance, that is, a reduced sensitivity to a succeeding heat treatment, has been noted in vitro and following local hyperthermia in normal tissues and malignant tumors. However, information is sparse concerning thermal tolerance following systemic hyperthermia, thereby limiting our ability to design optimally fractionated systemic hyperthermia treatment protocols. A technique for reproducibly inducing systemic hyperthermia in the rat is described, and the survival curve for rats exposed at 42.5 degrees C for periods of up to 75 minutes is presented. Using this system, increased survival of rats to systemic hyperthermia at 42.5 degrees C was demonstrated 30 hours after an initial sublethal conditioning exposure (41.8 degrees C for 1 hour). The LD50 (the time of exposure lethal to 50% of the rats) at 42.5 degrees C was increased by a factor of approximately 2 in the animals exposed to the sublethal conditioning. This increase in LD50 demonstrates the development of thermal tolerance to killing by whole body hyperthermia.