Although risk factors for cirrhosis in chronic hepatitis C virus (HCV) infection have been identified, the role of HCV-genotype 3 remains controversial, and limited data are available in drug users. The aim of the study was to assess risk factors for severe liver disease (cirrhosis/hepatocellular carcinoma) in HCV-infected drug users between 2001 and 2007 in France. Patients who reported drug use and who had been referred for HCV infection to hepatology centers from a national surveillance system were identified. The severity of liver disease was assessed clinically and histologically (Metavir score). Factors associated with severe liver disease were analyzed after estimating missing values by multiple imputation (MI). Of the 4,065 drug users naive to anti-HCV treatment who were referred to the 26 participating centers, 8.0% had severe liver disease, 25.7% were infected with HCV-genotype 3. Factors associated independently with an increased risk of severe liver disease were HCV-genotype 3 (adjusted odds ratio, multiple imputation (aORMI) = 1.6, [95% confidence interval, 95% CI: 1.2–2.1]), HIV infection (aORMI = 1.8, [1.2–2.8]), male sex (aORMI = 2.0, [1.4–2.8]), age over 40 years (aORMI = 2.1, [1.6–2.9]), history of excessive alcohol consumption (aORMI = 2.8, [2.1–3.7]), and duration of infection ≥18 years (aORMI = 2.9, [2.0–4.3]). This analysis shows that HCV-genotype 3 is associated with severe liver disease in drug users, independently of age, sex, duration of infection, alcohol consumption, and co-infection with HIV. These results are in favor of earlier treatment for drug users infected with HCV- genotype 3 and confirm the need for concomitant care for excessive alcohol consumption. J. Med. Virol. 82:1647–1654, 2010. 2010 Wiley-Liss, Inc.