Background: Interferon-induced depression represents a major complication in antiviral treatment of chronic hepatitis C virus (HCV) infection. Aim: To evaluate in a placebo-controlled study the efficacy of a selective serotonin reuptake inhibitor (SSRI) in HCV patients on antiviral therapy with interferon-associated depression. Methods: 100 HCV outpatients were included in a randomised, double-blind, placebo-controlled study. During interferon therapy (peginterferon alfa-2b plus ribavirin), depression was monitored using the Hospital Anxiety and Depression Scale (HADS). Patients with clinically relevant interferon-induced depression (HADS ⩾9) were randomly assigned to placebo or citalopram (SSRI, 20 mg/day). Results: In 28 patients (28%), HADS scores increased to >8 during interferon therapy. They were treated with placebo (n = 14) or SSRI (n = 14). HADS scores declined significantly in SSRI patients within four weeks of therapy (pConclusions: The findings demonstrate clearly that citalopram treatment is highly effective in HCV patients on interferon therapy, when initiated after the onset of clinically relevant depressive symptoms. This suggests that a general SSRI prophylaxis is not necessary in these patients.