The purpose of this study was to determine whether interferon-alfa (IFN-alpha) therapy benefits patients with transfusion-dependent thalassemia and chronic active hepatitis C, and whether their iron burden modifies the response to this therapy. We conducted a controlled trial of recombinant IFN-alpha (3 million units per square meter of body surface area, three times a week for 15 months) in 65 patients with thalassaemia major and chronic active hepatitis C; 14 of them were untreated control subjects. In 21 of the 51 treated patients, alanine aminotransferase values returned to normal within 6 months, and hepatitis C virus ribonucleic acid was no longer detected in serum; no changes were detected among control subjects. The response to IFN-alpha therapy was inversely related (p < 0.002) to the liver iron burden as assessed by atomic absorption, the histologic semiquantitative method, or both methods. During 3 years of follow-up, two responder patients had relapses. We conclude that IFN-alpha represents a useful therapeutic option for children with transfusion-dependent thalassemia and chronic active hepatitis C with a mild to moderate iron burden.