Background: The aim of this prospective study was to assess the incidence and risk factors for hepatitis C virus (HCV) infection in a group of drug users in northern and eastern France. Methods: Quarterly follow-up for 12 months or until HCV seroconversion was offered to 231 drug users who were negative for anti-HCV antibodies, anti-HIV antibodies, and HBsAg, and who had used intravenous drugs at least once in their lifetime. Serological testing for anti-HCV antibodies, HBsAg, and anti-HIV antibodies was performed at baseline and at the end of follow-up. A confirmatory serum anti-HCV ELISA was performed if anti-HCV antibodies were detected in saliva. At enrollment and at each follow-up visit, a questionnaire collecting demographic data and detailing drug use and injection practices was administered, and anti-HCV antibody testing was performed on a saliva sample. Results: Among the 231 subjects enrolled, 165 (71.4%) were followed up and underwent final HCV serology. The incidence of HIV seroconversion was zero, and that of HCV was 9% (95% CI; 4.6–13.4) person-years. The incidence was 11% (95% CI; 4.7–17.1) person-years in the subpopulation of current users (those who had injected at least once in the 6 months prior to enrollment). Multivariate analysis based on baseline data shows that only female sex was an independent predictor of HCV seroconversion. Based on follow-up data, multivariate analysis shows that only sharing syringes and cotton swabs were independent predictors of HCV seroconversion. The adjusted relative risk of seroconversion was estimated at 16.4 (95% CI; 1.4–190.6; p < 0.05) among users who shared cotton swabs and at 6.3 (95% CI; 1.1–35.4; p < 0.05) among those who shared syringes. Conclusion: The incidence of hepatitis C remains high despite preventive measures. This study highlights the role of syringe sharing and confirms that of cotton sharing.