Objective: To carry out a systematic review of the risk factors for, and incidence of, major depressive episode (MDE) related to antiviral therapy for chronic hepatitis C. Data Sources: The MEDLINE, PsycINFO, and Cochrane databases were searched to locate articles published from the earliest available online year until June 2011 using the keywords hepatitis C, interferon-alpha, peginterferon, pegylated interferon, depression, and mood and Boolean operators. Articles written in English, Spanish, and French were included. Study Selection: Prospective studies reporting incidence of interferon-alpha-induced MDE were included. At baseline, patients did not present a DSM-IV/ICD depressive episode, and evaluation was performed by a trained clinician. Twenty-six observational studies met the inclusion criteria. Data Extraction: Extracted data included authors, year of publication, design, characteristics of the population, viral coinfection, adjunctive psychopharmacology, instruments to assess depression, dose and type of interferon-alpha, adjunctive ribavirin treatment, and follow-up time. Outcome of incidence of MDE (primary outcome measure) was abstracted, as were potential predictive variables. Data Synthesis: A full review was performed. Meta-analysis of the cumulative incidence of induced MDE as a function of time was carried out. Odds ratios (ORs) and mean differences were used to estimate the strength of association of variables. Results: Overall cumulative incidence of depression was 0.25 (95% CI, 0.16 to 0.35) and 0.28 (95% CI, 0.17 to 0.42) at 24 and 48 weeks of treatment, respectively. According to our analysis, high baseline levels of interleukin 6 (mean difference = 1.81; 95% CI, 1.09 to 2.52), female gender (OR = 1.40; 95% CI, 1.02 to 1.91), history of MDE (OR = 3.96; 95% CI, 2.52 to 6.21), history of psychiatric disorder (OR = 3.18; 95% CI, 1.60 to 6.32), subthreshold depressive symptoms (mean difference = 0.96; 95% CI, 0.31 to 1.61), and low educational level (mean difference = -0.99; 95% CI, -1.59 to -0.39) were predictive variables of MDE during antiviral treatment. Conclusions: One in 4 chronic hepatitis C patients who start interferon and ribavirin treatment will develop an induced major depressive episode. Clinicians should attempt a full evaluation of patients before starting antiviral treatment in order to identify those at risk of developing interferon-induced depression. © Copyright 2012 Physicians Postgraduate Press, Inc.