Although social networks are known to play an important role in drug-using behaviours associated with hepatitis C virus (HCV) infection, literature on social networks and HCV is inconsistent. This exploratory study examined HCV RNA distribution within a social network of anti-HCV-positive non-medical prescription opioid users (NMPOUs) in rural Appalachia. Participants were tested serologically for HCV RNA, and behavioural, demographic, and network data were collected using interview-administered questionnaires. Multivariate analyses were performed using logistic regression. Behavioural and demographic characteristics did not differ by RNA status. In the multivariate model, recent injecting drug users (IDUs) were more likely to be RNA positive [odds ratio (OR) 4·06, 95% confidence interval (CI) 1·04-15·83], and turnover into an IDU's drug network was significantly protective (OR 0·15, 95% CI 0·03-0·75). This is the first study to date to examine HCV distribution in rural NMPOUs from a network perspective and demonstrates that network characteristics significantly contribute to the epidemiology of HCV in this understudied, high-risk population.