Purpose: Currently the most effective treatment for hepatitis C is the combination of PEG interferon alpha and ribavirin; unfortunately, interferon can induce depression and is a major reason for avoiding or discontinuing treatment. The purpose of this study was to: 1) determine whether patients with a history of major depression could complete a course of peginterferon alpha-2a and ribavirin for hepatitis C, if first treated with escitalopram, and 2) estimate the relapse rate of depression during treatment with peginterferon alpha-2a and ribavirin in subjects pre-treated with escitalopram. Methods: Ten patients with major depression, in remission, were treated with escitalopram during peginterferon and ribavirin therapy. Escitalopram 10 mg/day was initiated 4 weeks prior to, and continued throughout interferon therapy. Dosage adjustments were made as needed. The Hamilton Depression Rating Scale (Ham-D), the Medical Outcomes Short Form and the Hopkins Symptom Checklist-90 were administered, along with other measures at pre-baseline, baseline, and 2,4,8,12,16,20,24,32,40,48 weeks. Results: No statistically significant increases in mean Ham-D scores were observed. Depression relapse was defined as Ham-D score of 15 or greater. Mean Ham-D score prior to initiation of treatment was 3.90 (95% CI 2.17–5.63, p= 0.3874). Highest mean score during treatment was 8.22 (95% CI 4.33–12.12, p= 0.568), observed at week 16. Nine of 10 subjects (90%) completed their course of interferon alpha and ribavirin without significant psychiatric complications. One subject was terminated following substance abuse relapse at week 14. Two subjects had pathologic Ham-D scores of 15 and 17 at weeks 12 and 24, respectively. One of these subjects was the subject who was terminated for substance abuse relapse. Eight of 10 subjects maintained Ham-D scores <15, throughout the entire study. Mean escitalopram dosage at endpoint was 15.5 mg daily. Nine of the ten patients cleared their virus at the end of treatment. Conclusions: Pre-treatment with escitalopram in subjects with major depression, in remission, may allow for completion of a course of interferon and ribavirin therapy for hepatitis C, without significant recurrence of depression symptoms.