Treatment of chronic hepatitis C with interferon alpha (IFN-α) is relatively contraindicated in patients with psychiatric disorders because of possible severe psychiatric side effects. We report on a case of a female patient with a chronic schizoaffective psychosis, who was treated for 3 months with 3 × 3 mio IE IFN-α s.c./week because of a chronic hepatitis C (genotype 1b). Psychosis was stable with flupentixol monotherapy. After 2 months, she developed a severe depressive syndrome which lead to suicidal ideation. Until this time, she was without any antidepressive medication. Depressive symptoms disappeared after interferon therapy was stopped. Under prophylactic treatment with low-dose trimipramine (50 mg) or nefazodone (200 mg/day) therapy with IFN-α 3 × 3 mio IE/week was re-established after several months and again 2 years later adding ribavirin 1200 mg/day, a virustaticum. In contrast to the symptoms during monotherapy with IFN-α, during the time of both combination treatments, no psychiatric side effects occurred. While for ribavirin antidepressant effects are not known, we suppose that antidepressants may prevent changes in serotonergic or noradrenergic neurotransmission caused by IFN-α.