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Objective: The aims of this prospective study were to investigate temporal changes in mood status and distress level, as well as the development of depression, during pegylated interferon (PEG-IFN)-based treatment of patients with chronic hepatitis C (CHC). We also explored whether baseline demographic, psychiatric, and personality traits predicted the evolution of depression. Methods: CHC patients without depression were screened with laboratory tests; psychiatric interviews; and evaluations of mood symptoms, level of distress, and personality traits. A total of 67 treatment-naïve patients with CHC were consecutively treated with PEG-IFN-α-2a plus ribavirin for 48 (genotype 1, n=29) or 24 (genotype 2, n=38) weeks. Patients were followed prospectively every 4 weeks during the treatment period. Results: Seven patients (10.4%) were diagnosed with major depressive disorder (MDD), and eight (11.9%) developed subsyndromal depression. Times to onset of MDD and subsyndromal depression were 6.67±5.01 and 11.11±5.58 weeks, respectively, after initiation of treatment. Patients who developed MDD had significantly increased fatigue and anxiety and poor psychological well-being during the course of treatment. Pretreatment subthreshold mood symptoms were a significant predictor of depression. Conclusion: An early psychiatric assessment may be helpful in improving psychological well-being in those with CHC, leading to adherence to PEG-IFN-based treatment.