Objective Our purpose was to assess whether participation in needle exchange programs (NEPs) influenced incident hepatitis C virus (HCV) infection through effects on injection risk behaviors among young injection drug users (IDUs) in the United States. Methods Data were drawn from three multi-site studies carried out in four major cities that enrolled IDUs over the period 1994–2004. Bivariate and multivariate analyses were conducted to assess relationships among sociodemographic characteristics, NEP use, injection risk behaviors, and prevalent or incident HCV infection. Results Of the total participants (n = 4663), HCV seroprevalence was 37%; among those who initially tested negative and completed follow-up at three, six, or 12 months (n = 1288), 12% seroconverted. Nearly half of participants reported NEP (46%) use at baseline. Multivariate results showed no significant relationship between NEP use and HCV seroconversion. Controlling for sociodemographic characteristics, IDUs reporting NEP use were significantly less likely to share needles (aOR = 0.77, 95% CI = 0.67–0.88). Additionally, controlling for sociodemographic characteristics and program use, sharing needles, sharing other injection paraphernalia, longer injection duration, and injecting daily were all positively related to prevalent infection. Conclusions Our results suggest an indirect protective effect of NEP use on HCV infection by reducing risk behavior.