Hepatitis C represents a major public health challenge due to its chronic course and major complications (e.g. liver tumor and cirrhosis). New treatment strategies (pegylated interferon +/- ribavirin) have recently improved the prognosis except in case of poor compliance. Psychiatric comorbidity, especially affective disorders, is commonly associated with hepatitis C and constitutes the main cause of poor compliance and treatment contraindication. The primary aim of our study was to emphasize the utility of a multi-disciplinary approach including psychiatric evaluation and preventive follow-up. The secondary objective was to show that a previous history of depression or attempted suicide should not be considered as a formal contraindication prohibiting the implementation of a specific follow-up. Fifty interferon treated patients were included in a prospective study: 20 were seen in an emergency setting in a context of anxiety or major depressive disorders after the initiation of the interferon treatment and 30 were followed on a systematic basis prior to the initiation of the interferon treatment. Our data confirm the high rate (52%) of major depressive disorders among the population of hepatitis C treated patients. A previous history of alcoholism might be predictive of such a complication. According to the subjective feeling of patients with previous break'off treatment associated with major depressive disorders, specific psychiatric follow-up may improve tolerance for the treatment. In conclusion, a previous history of depressive disorder or attempted suicide should not be considered as a contraindication, but should imply a specific psychiatric follow-up especially when alcoholism and previous break'off treatment are reported.