BACKGROUND Despite evidence suggesting that the majority of patients with hepatitis C virus (HCV) have psychiatric and substance use disorders, patients with these comorbidities have historically been excluded from antiviral therapy for HCV. OBJECTIVE The authors compared antiviral completion and sustained virologic response (SVR) rates between hepatitis C (HCV) patients with versus those without preexisting major depressive disorder (MDD). METHOD The authors performed a chart review of HCV patients (30 with MDD and 25 control subjects) who attended an optional HCV education class and signed informed consent allowing collection of clinical data. RESULTS The MDD group had completion and SVR rates similar to those of control subjects. Neuropsychiatric side effects and reasons for discontinuation of treatment were not different between groups. CONCLUSION Patients with MDD can be safely and effectively treated with antiviral therapy.