Patients with hepatitis C viral infection (HCV) have higher rates of baseline psychiatric disorders. Screening for HCV must be considered for patients in psychiatric practice, particularly when risk factors exist, and in older, less educated males with substance use histories. Close collaboration with a psychiatrist is recommended for patients with co-morbid psychiatric history. Many clinicians advocate prophylactic antidepressants for patients with a history of severe depression or previous depression with interferon (IFN) therapy. The primary treatment for IFN-induced depression is traditional antidepressant therapy; however, a number of adjuvant medications have been utilized to assist with symptomatic relief. Mania may emerge with IFN therapy, during discontinuation of IFN, and with the addition of antidepressants during the treatment course. Once the causes of IFN-induced depression and neuropsychiatric symptoms are better elucidated, a cocktail of adjuvant medications may be developed to minimize side effects.