Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. Objective A successful psychoeducation program for serious mental illness, PsychoEducation Responsive to Families (PERF), was modified for hepatitis C virus (HCV). An effectiveness study was carried out comparing HCV-PERF with didactic education. Patients and methods A sample of 309 adult HCV patients was recruited from three outpatient settings and randomized (60% HCV-PERF, 40% didactic control). Groups met for 90 min bimonthly for 6 months following separate structured protocols. HCV-PERF sessions included a didactic curriculum developed uniquely for groups by member choice, with group problem-solving and support interactions. Patients were assessed at baseline, after the intervention, and 1 year later. Demographic and HCV-related variables and structured diagnostic interview data were obtained. Results Both groups improved significantly on major depression and alcohol and drug use, quality of life, risk behaviors, and treatment satisfaction, and worsened on disability and perceived HCV-related problems. Intervention groups did not differ on outcomes. Conclusion Even though the active intervention did not achieve a significant improvement relative to the control condition, the observable improvements in both conditions warrant further exploration of the contributions of education and support as potentially important elements of HCV behavioral intervention. Further study is needed to identify elements common to education interventions that may be contributory to the improved outcomes over time.