Patients with chronic hepatitis C and low serum and hepatic iron stores may have an improved response to interferon (IFN). We tested whether iron reduction before and during IFN therapy would lead to an improved sustained biochemical and virological response compared with IFN alone. Eighty-two previously untreated patients with chronic hepatitis C were randomized to either: group A IFN-α2b 3 MU 3 times per week for 6 months, or group B iron reduction before and during IFN-α2b 3 MU 3 times per week for 6 months. Group B patients had lower mean serum alanine transaminase (ALT) levels than group A patients during treatment and follow-up. Group B patients had significantly lower mean hepatitis C virus (HCV)-RNA levels at treatment weeks 4 and 12 (P < .05). Serum HCV RNA was undetectable at the end of treatment in 15 group B patients compared with 7 group A patients (P = .03); 7 group B patients and 3 group A patients had persistently undetectable serum HCV RNA 24 weeks after the end of therapy (P = .20). Paired pre- and posttreatment liver biopsies in 18 group B patients demonstrated significant improvements in 2 of the 3 inflammation scores of the Knodell histological activity index (P < .05). No changes occurred in the paired biopsies from 15 group A patients. We conclude that iron reduction via therapeutic phlebotomy improves the end-of-treatment virological and histological response to short-term IFN therapy. Additional studies are needed to determine if iron reduction in combination with higher doses or longer duration of IFN may be of benefit.