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To review current literature on the effectiveness of preventive antidepressant treatment in patients with Chronic Hepatitis C (CHC) treated with pegylated interferon (IFN)-alpha and ribavirin.We identified studies published from 2001 to May 2013 that evaluated the effectiveness of preventive antidepressant use in patients with CHC treated with IFN. We excluded studies that focused on symptomatic treatment.Nine studies were found. Five of the nine clinical trials reported positive effects of an antidepressant agent in the prevention of IFN induced depression. Two yielded negative results, and one had inconclusive findings. Three studies had either no control arms, or did not include any information about randomization or blinding. Nearly all of the studies excluded patients with previous psychiatric history. Most of the early studies had limited sample sizes. Only two studies reviewed had a sample size larger than 100 patients. Follow-up period varied broadly in the different studies, ranging from 12 to 72 weeks. The two studies with the largest samples yielded contradictory results. The effect sizes ranged widely, some studies showed marginal improvement, and others found a highly significant improvement in the prevention of interferon induced depression. Patient attrition was high in most of the studies, and was similar in treatment and control arms.Data on the effectiveness of preventive antidepressant use for IFN induced depression in CHC patients is limited and inconclusive. There is still a clear need for further studies with larger sample sizes and rigorous methodology to draw conclusions and make a clear recommendation for preventive antidepressant treatment in all CHC patients receiving IFN.