We have treated 6 chronic alcoholics and identified an additional 19 reported in the literature who developed severe hepatotoxicity from acetaminophen taken in apparently moderate doses. The clinical disease in these 25 patients had a characteristic pattern: mild to moderate jaundice; mild to severe coagulopathy; and strikingly abnormal aminotransferase levels, values inconsistent with either acute alcoholic hepatitis or viral hepatitis. The possible causes for the injury from ostensibly nontoxic drug levels appear to be either the induction by chronic alcohol intake of the cytochrome P-450 system responsible for converting acetaminophen to a toxic metabolite, or the effect of alcoholism and the associated malnutrition in reducing the glutathione concentration, responsible normally for preventing hepatotoxicity by conjugation with the toxic metabolite. The research data pertaining to the apparent enhanced toxicity from chronic alcoholism are reviewed. Despite the low frequency of ethanol-potentiated acetaminophen hepatotoxicity, alcoholics should be cautioned about the use of acetaminophen while they persist in heavy consumption of alcohol.