Chlorpromazine increases the sensitivity of cells to doxorubicin; in vivo it also produces hypothermia, which has the contrary effect. To determine the net effect of these factors, we tested the toxicity of doxorubicin in mice which had developed chlorpromazine-induced hypothermia. Groups of 10 female Swiss albino mice received chlorpromazine (5 mg/kg sc). One hour later, when rectal temperature was 30 degrees C, doxorubicin. HCl (20 mg/kg ip) was injected. Median survival time was 10 +/- 2 days for controls and 48 +/- 5 days for chlorpromazine treated mice (4 experiments each). A high chlorpromazine dose (100 mg/kg) did not protect. Chlorpromazine (5 mg/kg) also reversed the slowing of weight gain by 5 mg/kg doxorubicin. If the drop in rectal temperature was prevented by keeping the mice at 32-35 degrees C, the protection by chlorpromazine was abolished. The results show that chlorpromazine protects against the toxicity of ip doxorubicin; the hypothermia produced by chlorpromazine seems to be essential for the protection.