OBJECTIVES: Transfusion-acquired chronic hepatitis C infection and systemic iron overload are common in patients with β thalassemia major. The magnitude of hepatic iron overload has been associated with a poor response to interferon-based antiviral therapy for hepatitis C. The aim of this study was to evaluate the effect of hepatic iron concentration (HIC) on response to interferon monotherapy in patients with massive hepatic iron overload. METHODS: Twenty-eight patients with β thalassemia major, transfusion-acquired iron overload, and chronic hepatitis C infection were prospectively treated with interferon for 6 months. HIC was measured by atomic absorption spectroscopy before treatment. Serum iron, ferritin, hepatitis C virus genotype, viral load, and liver histology were analyzed. RESULTS: Eight patients (28%) achieved a sustained virological response that has been durable after a mean of 66 months of follow-up. The median HIC was 2583 μg/g dry weight. There was no difference in HIC between responders and nonresponders to therapy. Serum hepatitis C virus RNA was lower in responders than in nonresponders. Genotype 1 was more frequent in nonresponders, and non-1 genotypes were more frequent in responders, although this did not reach statistical significance because of patient numbers. CONCLUSIONS: A long term response to interferon is unrelated to HIC in this patient group, and a durable response can occur despite massive iron overload. HIC may be a factor in liver cell injury, but it does not reliably predict a response to interferon therapy.