Depression and irritability, but also psychosis and attempted or successful suicides, are reported during interferon (IFN) therapy. IFN schedule and history of psychiatric illness are not enough to predict who will develop symptoms. Aims. To assess the prevalence of depression during IFN-therapy; to test whether a computerized version of the Minnesota-Multiphasic-Personality-Inventory (MMPI) is a reliable test for the early identification of patients at risk of depression before IFN-therapy is started; and whether and how the depression can be cured. Patients. 185 patients treated with interferon and ribavirin for chronic hepatitis C. Methods. Before therapy, all patients underwent an MMPI and a clinical examination, specifically for the identification of depressive symptoms. Results. Thirty-one patients developed a psychiatric disorder, 11 of them requiring treatment with antidepressant drugs. Among the 18 patients with MMPI positive tests, 16 developed a psychiatric disorder, 8 a severe disorder (sensitivity of 0.58; 0.73 for severe disorders).Among the 154 who did not develop psychiatric side effects, 152 had a negative MMPI (specificity: 0.99). Severe psychiatric disorders were successfully treated with antidepressant drugs. Conclusions. Psychiatric side effects are easy to see during IFN-therapy. Psychiatric evaluation should be considered on all patients before treatment. However, as specific examination cannot always be performed because of the lack of psychiatrists in liver units, it is necessary to identify tests, easy to carry out, reproducible, self-administered and inexpensive in order to screen all patients. If depression develops, it should be treated aggressively, and selective serotonin re-uptake inhibitors are the anti-depressant of choice.