Introduction: Effective treatment regimens exist for the hepatitis C virus (HCV); however, clinicians are often resistant to evaluation or treatment of patients with alcohol or substance abuse problems. We describe a continuing medical education (CME) program for clinicians in a nationwide health care system, with emphasis on current treatment practices, multispecialty collaboration, and organizational change. Methods: Quantitative measures were used to assess changes in knowledge and treatment confidence, and site-specific organizational changes were qualitatively evaluated. The CME program included a preassessment of current HCV knowledge and care; a 2-day preceptorship; and follow-up with coaching calls at 1, 3, and 6 months. Program attendees included 54 medical and mental health providers from 28 Veterans Affairs Medical Centers. Results: Knowledge following the CME program increased significantly. In 93% of the sites, there were organizational changes such as HCV support group-initiated group education, in-service training, improvement in patient notification or scheduling processes, hiring of new clinical staff, development of a business plans, and discussions about changes with administration. Of all sites, 15 (54%) changed existing antiviral treatment protocols, 18 (64%) established collaborative relationships, and almost half (13/28) established regular use of depression and alcohol use screening tools. Major barriers to change included lack of administrative support or resources (or both) and difficulty collaborating with mental health colleagues. Discussion: This multifaceted CME program with follow-up coaching calls significantly increased individual knowledge and confidence scores and resulted in improved clinic processes and structures. Organizational change was facilitated by the development of an action plan. The major change agent was a nurse; the primary deterrent was an administrator.