The present study investigated the toxicity of repeated subcutaneous cocaine administrations combined with oral doses of ethanol, and discussed the role of the toxic metabolite cocaethylene. Subcutaneous cocaine (70 mg/kg) was given to male ICR mice at 45 min after an oral administration of either ethanol (maximum 3 g/kg) (cocaine-ethanol group; n = 50) or saline control (cocaine group; n = 30), once per day, for up to 5 days. In the combined cocaine-ethanol group, the total frequency of death was significantly increased (86%) as compared to the cocaine group (40%). In both administration groups, regardless of the day of death, "late" deaths characterized by the late and unexpected onset of fatal symptoms could be differentiated from "early" deaths on the basis of the survival time after the last cocaine injection, the drug concentrations in the tissues at the time of death, and/or the observed physical disorders. In the combined cocaine-ethanol group, a late death group with survival times exceeding 12 hr and two early death groups could be differentiated, based on the presence or absence of cocaethylene and the different types of clinical symptoms. In the early death group in which cocaethylene could be detected, the volume of ethanol ingested was not significantly different from the late death group with large ethanol consumption and slow exacerbation of the respiratory and locomotive symptoms. Furthermore, the severity of the cocaine-induced seizures was also similarly decreased by ethanol. In the other early death group in which cocaethylene could not be detected, the volume of ethanol ingested was significantly lower than in the late death group, and seizures as severe as in the cocaine-only group were observed.