The primary purpose of the present investigation was to evaluate if the presence of ethanol increased lethality induced by propoxyphene. A secondary aim was to study the effect of naloxone on propoxyphene lethality alone, and on the concomitant administration of propoxyphene and ethanol. Male Wistar rats (210–330 g) were used as test animals. Propoxyphene (175 mg/kg) and ethanol (2 g/kg) were administered by gastric intubation, naloxone (2 mg/kg) by subcutaneous injection. Four groups, each consisting of 19 rats, received either of the following drug treatments: Propoxyphene, ethanol + propoxyphene, naloxone + propoxyphene, and naloxone + ethanol + propoxyphene respectively. The drugs were given in the sequence mentioned at the beginning of the experiment. Naloxone was also given 45 and 90 min later. Mortality was reduced to 42% in the group that received ethanol and propoxyphene compared to 73% in the group that received propoxyphene only. Naloxone protected against lethality in both groups. Some animals died despite naloxone administration, possibly due to a nonopioid cardiotoxic effect of propoxyphene or its metabolite. An increase in the propoxyphene/norpropoxyphene (P/N) ratio due to an increase in the absolute concentrations of propoxyphene and a decrease in the absolute levels of norpropoxyphene in blood, brain, and heart tissues was observed in the ethanol + propoxyphene group, compared to the propoxyphene group. In the animals which died, the highest P/N ratio was observed in brain tissue and the lowest in heart muscle. Despite the pharmacokinetic data obtained in this investigation indicating impaired propoxyphene metabolism in the presence of ethanol, ethanol did not enhance propoxyphene-induced lethality. This is also contrary to suggestions from previous studies. Our results demonstrate that at least in one species and at one dose ratio (ethanol/propoxyphene) ethanol might reduce the lethality caused by propoxyphene alone. This suggests some kind of antagonism between the two drugs, probably in the central nervous system.