To determine whether chronic high-dose (80 to 120 mg/day) methadone treatment would exert hepatotoxic effects on patients with or without liver disease, the first 214 patients admitted for maintenance therapy were studied prospectively; 129 were still in treatment after 3 or more years. There were no significant changes in tests of liver function with time and, therefore, no evidence of methadone hepatotoxicity. Of the group 23% had a history of hepatitis, and 25% were moderate to heavy users of ethanol. Minimal to moderate abnormalities of liver function tests were present in 57% at admission and in 51% after 3 or more years of treatment. Up to 49% had abnormalities in some protein tests throughout. The liver function abnormalities may be caused by chronic persistent or, less frequently, chronic aggressive hepatitis and, in some, by excessive usage of ethanol. Protein abnormalities may be owing to liver disease and altered immune status caused by injection of foreign substances.