Introduction: Hepatectomies may exacerbate chronic hepatitis B in patients with high hepatitis B viral (HBV) DNA levels, and could result in hepatic insufficiency. Antiviral treatment is effective for suppressing HBV virus loads. This study investigated whether perioperative antiviral therapy is warranted for resection of hepatocellular carcinoma (HCC) with concurrent HBV infections. Methods: Patients with HBV-related HCC (n = 112) who underwent major liver resection were retrospectively divided into two groups based on treatment with perioperative antiviral therapy (antiviral group) (n = 72) or absence of antiviral treatment (control group) (n = 40). Results: Exacerbation of chronic hepatitis B occurred in 6 patients of the control group (15.0%). The prevalence of hepatic insufficiency in the antiviral group and control group were 1.4% (1/72) and 12.5% (5/40), respectively (p < 0.05). Five of them (4.5%) developed hepatic encephalopathy and 3 of them (2.7%) developed hepatorenal syndrome. The control group had significantly higher morbidity (75.0% vs. 34.7%, p < 0.01) than the antiviral group. The control group had significantly higher levels of postoperative alanine aminotransferase (ALT) and serum bilirubin than the antiviral group. Conclusion: Perioperative antiviral treatment improves patient safety by decreasing morbidity and speeding recovery of postoperative liver function for HBV-related major HCC resection. (C) 2015 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.