The intraperitoneal injection of 5-hydroxytryptamine (5-HT) in unrestrained and unanesthetized mice held at 22C causes a hypothermia which is maximal after approximately 15 minutes. When mice injected with 5-HT were held in a controlled environment of 22C and 50% relative humidity and exposed to microwaves (2450 MHz, cw) at 1 mW/sq cm for 15 minutes, significant increases were observed in the body temperature of these mice compared to 5-HT-treated sham-irradiated mice. The magnitude of the response was related to power density (10 > 5 > 1 mW/sq cm). Saline-injected mice exposed for 15 minutes at 10 mW/sq cm (specific absorption rate = 7.2 mW/g) showed no significant increase in body temperature compared to saline-injected sham-irradiated mice. The hypothermia induced by 5-HT in mice was also found to be affected by ambient temperature alone. Increases in ambient temperature above 22C, in the absence of microwaves, caused a concomitant increase in body temperature. By altering the thermoregulatory capacity of mice with 5-HT, subtle heating by microwaves was detected. These results indicate that the interpretation of microwave-induced biological effects observed in animals at comparable power and absorption levels should include a consideration of the thermogenic potential of microwave radiation.