Background: Hepatocellular carcinoma (HCC) commonly recurs after surgical resection without effective adjuvant therapy. Pegylated interferon plus ribavirin has been shown efficacious in preventing the development of hepatitis C virus (HCV)-related HCC, but its efficacy in reducing HCC recurrence remains unknown. Objective: We aimed to investigate whether postoperative antiviral therapy reduced recurrence of HCVrelated HCC after resection. Methods: This population-based retrospective cohort study analyzed the Taiwan National Health Insurance Research Database. After screening 17,574 patients undergoing liver surgery for a first-time diagnosis of HCC between October 2003 and December 2008, we identified 893 patients with antiviral-na?ve HCV infection who had curative resection without recurrence within one year. Ninety five eligible patients received postoperative pegylated interferon plus ribavirin (treated cohort), and were matched 1:4 in age, gender, and cirrhosis status with 380 patients using no antiviral agent (untreated cohort). Patients were followed up for HCC recurrence and mortality since one year after surgery. Results: The HCC recurrence rate was significantly lower in the treated than the untreated cohort (32.39% versus 47.69% after 3 years of follow-up, p=0.004). With adjustment for multiple confounders including death occurring prior to HCC recurrence, the recurrence risk was reduced nearly by half (hazard ratio 0.52; 95% CI, 0.34-0.80) among treated patients. Multivariate stratified analyses confirmed antiviral therapy was consistently associated with attenuated risk of HCC recurrence across subgroups. Moreover, mortality was lower in the treated cohort significantly (1.92% vs. 17.68% after 3 years of follow-up, p=0.004). Conclusions: Postoperative pegylated interferon plus ribavirin is associated with reduced recurrence of surgically resected HCV-related HCC.