Progesterone increases cocaine's cardiovascular toxicity in sheep and rats. To determine whether progesterone enhances the lethality of cocaine, nonpregnant female rats were treated with either IM progesterone (P4) or vehicle, and pregnant rats (Preg) were untreated. The rats received one IP injection of cocaine at a dose between 25-75 mg/kg and were observed for seizures and/or death. All 62 rats that died did so within 17 min, preceded by seizures in 90.3%. Mean times-to-seizure and times-to-death, and mean lethal serum cocaine concentrations did not differ among groups. Serum progesterone levels (ng/ml +/- SEM) at the time of death were different among groups: 24 +/- 1.7 (C), 102 +/- 6.4 (P4), and 139 +/- 5.2 (Preg). Logistic regression dose/fatality curves, LD50s, and LD10s for the pregnant, progesterone, and control groups were not significantly different from one another. Though progesterone has enhanced cocaine's cardiac toxicity in some studies, it does not increase the risk of death from acute cocaine exposure in rats.