Eleven patients with chronic hepatitis D virus (HDV) infection who had chronic active hepatitis and HDV antigen on liver biopsy were randomised in a crossover therapeutic trial of interferon-alpha 2b vs. no therapy. Nine patients had a history of intravenous drug use (drug free > 6 months before therapy), 8 had histological evidence of cirrhosis, and 7 out of 10 tested were found to be seropositive for antibody to hepatitis C virus (HCV). Six patients were randomised to receive interferon-alpha 2b therapy for 1 year, and 5 patients received no therapy for 1 year followed by the same regime of interferon-alpha 2b treatment. All patients with a history of intravenous drug use found self-injection stressful, 3 patients restarted using illicit drugs, and 2 patients with active cirrhosis developed severe thrombocytopenia during therapy and treatment was stopped in these patients. Of the 6 patients who completed at least 11 months of treatment, 4 lost serum hepatitis B surface antigen (HBsAg) with 3 developing antibody to HBsAg and one patient completing treatment. Among the 6 patients who had posttreatment liver biopsy, 5 showed an improvement in liver histology (3 of them lost serum HBsAg). These results provide further evidence that interferon-alpha is beneficial in chronic HDV infection although the psychological stress associated with the treatment, especially in patients with a previous history of intravenous drug use, is not inconceivable.