Only limited data are available on selective serotonin re-uptake inhibitor (SSRI) prophylaxis for antiviral re-treatment in hepatitis C patients with previous interferon-induced major depressive episodes. Therefore, we investigated the efficacy and safety of secondary SSRI prophylaxis in these patients. In a prospective and longitudinal study, repeated psychometric testing (Hospital Anxiety and Depression Scale) was performed before, during, and after antiviral re-treatment. Chronic hepatitis C virus (HCV)-infected patients, who had been psychometrically monitored during an unsuccessful previous antiviral therapy, and had developed major depression were included. Interferon re-therapy with SSRI prophylaxis was started (n = 8). The reference group was comprised of HCV patients without a history of interferon-associated depression and also a group who were previously unsuccessfully treated with interferon and were re-treated without SSRI prophylaxis (n = 9). All patients receiving SSRI prophylaxis were able to complete interferon re-therapy as scheduled. As in the first therapeutic course, depression scores were significantly elevated during re-treatment also (P < 0.001). Depression scores were significantly lower (P =0.036) during interferon re-therapy with SSRI prophylaxis. Reference group subjects showed similar depression scores during first therapy and re-therapy (P > 0.05). In conclusion, hepatitis C patients with a history of interferon-induced major depression can be successfully re-treated with peginterferon/ribavirin and concomitant SSRI prophylaxis. In these patients, SSRI prophylaxis is safe and efficacious and should be considered, if antiviral re-therapy is indicated.