We investigated the possibility that chlorpromazine (CPZ), an antiemetic frequently used to control nausea and vomiting in cancer patients receiving chemotherapy, might modify the progression of the renal toxicity and lethality of cisplatin (CDDP). In mice the preadministration of CPZ (i.p.) 1 h prior to CDDP (i.p.) injection efficiently reduced not only the lethal toxicity, but also the renal (indicated by increased blood urea nitrogen values) and intestinal toxicity (indicated by the incidence of diarrhea) which are usually observed in mice treated with CDDP alone. To further study the apparent protective activity of CPZ against CDDP nephrotoxicity we chose rats a species more commonly used as a model for nephrotoxicity. In F344 rats, CPZ ameliorated CDDP-induced increases in blood urea nitrogen (BUN), urine glucose, protein and lactate dehydrogenase (LDH). The preadministration of CPZ had no observed effect on the antitumor activity of CDDP in mice inoculated i.p. with Sarcoma 180, EL-4 lymphoma, or P-388 leukemia cells. The present study suggest that CPZ may be of therapeutic benefit when used with CDDP. This study also provides a rational basis for the selection of antiemetic therapy.