Little research has examined etiological factors associated with pain in patients with the hepatitis C virus (HCV). The purpose of this study was to evaluate the relationship between biopsychosocial factors and pain among patients with HCV. Patients with HCV and pain (n = 119) completed self-report measures of pain, mental health functioning, pain-specific psychosocial variables (pain catastrophizing, self-efficacy for managing pain, social support), prescription opioid use, and demographic characteristics. In multivariate models, biopsychosocial factors accounted for 37% of the variance in pain severity and 56% of the variance in pain interference. In adjusted models, factors associated with pain severity include pain catastrophizing and social support, whereas variables associated with pain interference were age, pain intensity, prescription opioid use, and chronic pain self-efficacy (all p values <0.05). The results provide empirical support for incorporating the biopsychosocial model in evaluating and treating chronic pain in patients with HCV.