OBJECTIVES: We determined the factors associated with hepatitis C (HCV) infection among rural Appalachian drug users. METHODS: This study included 394 injection drug users (IDUs) participating in a study of social networks and infectious disease risk in Appalachian Kentucky. Trained staff conducted HCV, HIV, and herpes simplex-2 virus (HSV-2) testing, and an interviewer-administered questionnaire measured self-reported risk behaviors and sociometric network characteristics. RESULTS: The prevalence of HCV infection was 54.6% among rural IDUs. Lifetime factors independently associated with HCV infection included HSV-2, injecting for 5 or more years, posttraumatic stress disorder, injection of cocaine, and injection of prescription opioids. Recent (past-6-month) correlates of HCV infection included sharing of syringes (adjusted odds ratio = 2.24; 95% confidence interval = 1.32, 3.82) and greater levels of eigenvector centrality in the drug network. CONCLUSIONS: One factor emerged that was potentially unique to rural IDUs: the association between injection of prescription opioids and HCV infection. Therefore, preventing transition to injection, especially among prescription opioid users, may curb transmission, as will increased access to opioid maintenance treatment, novel treatments for cocaine dependence, and syringe exchange.