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AIM: Smoking may affect adversely the response rate to interferon-α. Our objective was to verify this issue among chronic hepatitis C patients.METHODS: Over the year 1998, 138 chronic hepatitis C male Egyptian patients presenting to Cairo Liver Center,were divided on the basis of smoking habit into: group Ⅰ which comprised 38 smoker patients (＞30 cigarettes/d)and group Ⅱ which included 84 non-smoker patients.Irregular and mild smokers (16 patients) were excluded.Non eligible patients for interferon-α therapy were excluded from the study and comprised 3/38 (normal ALT) in group Ⅰ and 22/84 in group Ⅱ (normal ALT, advanced cirrhosis and thrombocytopenia). Group Ⅰ was randomly allocated into 2 sub-groups: group Ⅰa comprised 18 patients who were subjected to therapeutic phlebotomy while sub-group Ⅰb consisted of 17 patients who had no phlebotomy. In sub-group Ⅰa, 3 patients with normal ALT after repeated phlebotomies were excluded from the study. Interferon-α 2b 3 MU/TIW was given for 6 mo to 15 patients in group Ⅰa, 17 patients in group Ⅰb and 62 patients in group Ⅱ.Biochemical, virological end-of- treatment and sustained responses were evaluated.RESULTS: At the end of interferon-α treatment, ALT was normalized in 3/15 patients (20%) in group Ⅰa and 2/17patients (11.8%) in group Ⅰb compared to17/62 patients (27.4%) in group Ⅱ (P=0.1). Whereas 2/15 patients (13.3%)in group Ⅰa. and 2/17 patients (11.8%) in group Ⅰb lost viraemia compared to 13/62 patients (26%) in group Ⅱ (P = 0.3). Six months later, ALT was persistently normal in 2/15 patients (13.3%) in group 1a and 1/17 patients (5.9%) in group Ⅰb compared to 9/62 patients (14.5%) in group Ⅱ (P= 0.47). Viraemia was eliminated in 1/15 patients (6.7%) in group Ⅰa and 1/17 patients (5.9%) in group Ⅰb compared to 7/62 patients (11.3%) in group Ⅱ, but the results did not mount to statistical significance (P = 0.4).CONCLUSION: Smokers suffering from chronic hepatitis C tend to have a lower response rate to interferon-α compared to non-smokers. Therapeutic phlebotomy improves the response rate to interferon-α therapy among this group.