Severe liver failure developed in three chronic alcoholics after they ingested acetaminophen for therapeutic reasons. The clinical course was characterized by SGOT levels of 5,000 to 10,000 IU. Concomitant renal failure developed in two of these patients, and one died in hepatic coma. To determine whether alcohol enhances acetaminophen hepatotoxicity, a lethal dose for 50% survival of a test group (LD50) was performed for mice fed 10% alcohol in their water supply for three weeks and for mice receiving a normal diet only. A significant reduction in the LD50 was seen in the alcohol-pretreated mice, and correlations were noted between histological findings in the liver and the LD50 data. These findings suggest that alcohol enhances acetaminophen hepatotoxicity in mice and provides supportive evidence that these three alcoholic patients probably had a similar pathophysiological basis for their liver disease.