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Hepatitis C virus (HCV) infection is causally associated with insulin resistance and diabetes mellitus. This population-based cohort study aimed to investigate whether antiviral therapy for HCV infection was associated with improved clinical outcomes related to diabetes. From the Taiwan National Health Insurance Research Database, 2,267,270 Taiwanese residents diagnosed with diabetes mellitus were screened for eligibility. HCV infection was defined by a specific diagnosis code and measurement of serum antibody. After excluding patients with serious comorbidity, we enrolled a total of 1,411 eligible patients who received pegylated interferon plus ribavirin (treated cohort), and matched them 1:1 with 1,411 untreated controls by propensity scores (untreated cohort). We also matched the treated cohort 1:4 with 5,644 diabetic patients without HCV infection (uninfected cohort). Participants were followed up for the occurrence of endstage renal disease (ESRD), ischemic stroke, and acute coronary syndrome (ACS) after receiving antiviral treatment or the corresponding calendar date. From 2003 to 2011, the 8-year cumulative incidences of ESRD in the treated, untreated, and uninfected cohorts were 1.1% (95% confidence interval [CI], 0.3-2.0%), 9.3% (95% CI, 5.9-12.7%), and 3.3% (95% CI, 2.3-4.3%), respectively (P < 0.001); those of stroke were 3.1% (95% CI, 1.1-5.0%), 5.3% (95% CI, 3.0-7.5%), and 6.1% (95% CI, 4.8-7.4%), respectively (P = 0.01); and those for ACS were 4.1% (95% CI, 2.1-6.1%), 6.6% (95% CI, 3.7-9.5%), and 7.4% (95% CI, 5.9-9.0%), respectively (P = 0.05). As compared with the untreated cohort, antiviral treatment was associated with multivariate-adjusted hazard ratios of 0.16 (95% CI, 0.07-0.33%) for ESRD, 0.53 (95% CI, 0.30-0.93) for ischemic stroke, and 0.64 (95% CI, 0.39-1.06) for ACS. Conclusion: Antiviral treatment for HCV infection is associated with improved renal and cardiovascular outcomes in diabetic patients. (Hepatology 2014;59:1293-1302)