Chronic delta hepatitis is an uncommon but severe form of chronic viral hepatitis for which there is currently no satisfactory therapy. A patient with chronic delta hepatitis was treated with interferon alfa, 5 million units daily for 12 years. Serial serum samples were tested for routine liver tests and selected samples for quantitative levels of hepatitis B surface antigen (HBsAg) and hepatitis delta virus RNA. Liver biopsies were performed before, during, and after an initial 1-year course of therapy and again after 3 and 10 years of continuous therapy. With initiation of interferon therapy, serum aminotransferase levels decreased to normal range, became abnormal again when the dose was reduced, and increased to pretreatment levels when therapy was stopped. With reinstitution and prolonged therapy, aminotransferase levels became persistently normal; after several years, both hepatitis delta virus RNA and serum HBsAg became undetectable. Liver biopsy, which initially revealed cirrhosis, showed gradual improvement in inflammatory and fibrosis scores and, after 10 years, no abnormalities or fibrosis. Therapy was stopped, and the patient remained free of evidence of infection. In conclusion, long-term therapy with interferon alfa in high doses led to resolution of chronic delta hepatitis, disappearance of hepatitis delta and B virus markers, and improvement in fibrosis.