Abstract Background Transmission of hepatitis C vims (HCV) is strongly associated with use of contaminated blood products and injection drugs. Other "non-parental" modes of transmission including sexual activity have been increasingly recognized. We examined risk factors for acquiring HCV in patients who were referred to two tertiary care centers and enrolled in an antiviral therapy protocol. Methods Interviews of 148 patients were conducted apart from their physician evaluation using a structured questionnaire covering demographics and risk factors for HCV acquisition. Results Risk factors (blood products, injection/intranasal drugs, razor blades/ toothbrushes, body/ear piercing, occupational exposure, sexual activity) were identified in 141 (95.3%) of participants; 23 (15.5%) had one (most frequently blood or drug exposure), 41 (27.7%) had two, and 84 (53.4%) had more than two risk factors. No patient reported sexual activity as a sole risk factor. Body piercing accounted for a high number of exposures in women. Men were more likely to have exposure to street drugs but less exposure to blood products than women. Blood product exposure was less common in younger than older HCV patients. Conclusion One and often multiple risk factors could be identified in nearly all HCV-infected patients seen in a referral practice. None named sexual transmission as the sole risk factor. The development of a more complete profile of factors contributing to transmission of HCV infection may assist in clinical and preventive efforts. The recognition of the potential presence of multiple risk factors may have important implications in the approach to HCV surveillance, and particularly the use of hierarchical algorithms in the study of risk factors.