A previous report has indicated that progesterone pretreatment can markedly reduce cadmium toxicity in male NAW mice. Therefore we examined the effects of progesterone pretreatment on cadmium toxicity in male Fischer (F344/NCr) rats. A single sc injection of 20 mumol CdCl2/kg proved nonlethal over 24 hr but caused the typical spectrum of testicular lesions in these rats. However, when rats were pretreated with progesterone (100 mg/kg, sc, -48, -24, and 0 hr) and then given cadmium (20 mumol CdCl2/kg, 0 hr), this dose of cadmium proved very toxic, unexpectedly causing a 53% mortality. Progesterone pretreatment had no effect on cadmium-induced testicular lesions in surviving rats. Significant elevations in serum lactate dehydrogenase (LDH) activity, indicative of hepatotoxicity, were also observed in progesterone-pretreated rats given cadmium as compared to rats given cadmium alone. Progesterone pretreatment had no effect on the distribution of cadmium to liver, kidney, or testes. Progesterone pretreatment also had no effect on the cadmium-induced increases in hepatic or renal metallothionein (MT) or hepatic or testicular MT mRNA levels. In contrast, levels of the testicular cadmium-binding protein (TCBP) in progesterone-pretreated rats were doubled. These results indicate that, contrary to previously reported data for the mouse, progesterone pretreatment increased the lethality of cadmium in male Fischer (F344/NCr) rats and had no effect on cadmium-induced testicular toxicity. The mechanism by which progesterone enhanced cadmium toxicity, especially cadmium-induced hepatotoxicity, deserves further study.