OBJECTIVES: The aim of this study was to determine the longitudinal effects of selective serotonin reuptake inhibitor (SSRI) therapy and cytokine-related depression on levels of hepatitis C virus (HCV) during treatment with combination therapy. BACKGROUND: Prior studies have investigated the association between cytokine-related depression and sustained virological response, but it is unknown whether anti-inflammatory properties of SSRIs used to treat cytokine-related depression inadvertently contravene proinflammatory properties of pegylated interferon (Peg-IFN), in effect reducing therapeutic efficacy. STUDY: In a retrospective cohort design, patients being treated with Peg-IFN or interferon in combination with ribavirin at a gastroenterology clinic were followed from initiation of therapy until 24 weeks after the completion of therapy. Sustained virological response and rate of decline of HCV RNA levels were compared among patients with SSRI therapy and cytokine-related depression. RESULTS: Selective serotonin reuptake inhibitor therapy and cytokine-related depression did not adversely impact the proportion of patients achieving sustained virological response. In a multivariate longitudinal analysis, the mean slope of HCV RNA levels declined faster over time in patients without cytokine-related depression in comparison to patients with cytokine-related depression (P = 0.05), and the mean slope of HCV RNA levels declined similarly over time in patients with and without SSRI therapy. CONCLUSIONS: In this retrospective cohort, SSRI therapy did not interfere with immune activation dynamics of Peg-IFN/ribavirin, and patients without cytokine-related depression developed quicker responses and suppressed HCV replication more favorably over time. © 2014 Lippincott Williams & Wilkins.