In order to elucidate changes in thyroid hormone metabolism during acute heat stress, we measured sequentially serum thyroxine (T4), triiothyronine (T3), and reverse T3 (rT3) levels in 5 patients with neoplasia during treatment with whole body hyperthermia. The core temperature was raised from 37.0 degrees C to 42.0 degrees C over a 2-hour period, maintained at 42.0 degrees C for 2 hours, and then cooled to 37.0 degrees C over 2 hours. This short period of severe hyperthermia produced a fivefold rise in rT3 and a fall in T3 levels to one half of baseline levels. T4 and free T4 levels increased slightly, but thyrotropin (measured in two patients) did not change. These changes in T3 and rT3 levels were detectable at the fourth hour after onset of hyperthermia, were maximal at 24 and 48 hours, and in one patient were uncorrected after 4 days. We conclude that this reciprocal change in T3 and rT3 levels is a response to stress and may represent in part adaptation to a high environmental temperature by the suppression of theromengic T3. Whole body hyperthermia of short duration for cancer therapy produces profound changes in the peripheral degradation of thyroxine, which last for several days. This must be considered in the management of patients receiving hyperthermia, and the technique itself may prove to be a useful model for the study of adaptation to heat stress.