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Treatment of rheumatic diseases with concurrent hepatitis C virus (HCV) infection is a therapeutic challenge. Etanercept has no known hepatotoxicity; however there is a concern for worsening of HCV infection–related liver disease due to immunosuppressive action of the drug. Here, we retrospectively assessed the safety of etanercept in rheumatologic disease in patients with chronic HCV.A retrospective review was conducted in patients with chronic HCV infection who received etanercept for diagnosis of rheumatoid arthritis and psoriatic arthritis. The primary end point was a serum transaminase level of at least 3 times the upper limit of normal during etanercept therapy. We also recorded HCV RNA load.Fourteen patients met the inclusion criteria. Mean age was 52 (SD, 8) years. The median follow-up period after initiation of etanercept was 105 months (range, 13–132 months). During follow-up, 7 of 14 patients had elevation of aspartate aminotransferase and/or alanine aminotransferase 3 times the upper limit of normal. Two of 7 patients had concomitant elevation in transaminases and increase in HCV viral load during etanercept exposure, which could not be attributed to other hepatotoxic disease-modifying antirheumatic drugs. In both patients, transaminase levels normalized upon etanercept discontinuation.In contrast to the majority of previous shorter-duration studies, 2 of 14 patients in our series had possible HCV-related worsening of liver disease while on etanercept therapy. Although no firm conclusion can be drawn, it appears that HCV infection can worsen while on etanercept therapy, and therefore, we propose these patients should be monitored serially.