Abstract Purpose The aim of this prospective cohort study was to investigate the impact of preoperative hepatitis B viral load, as well as postoperative antiviral therapy, on the risk of long-term survival after curative resection of hepatitis B virus-related hepatocellular carcinoma (HCC). Methods A prospective cohort of hepatitis B virus-related HCC patients undergoing curative resection from 2002 to 2008 was studied. According to preoperative viral load (using 10,000 copies/mL of hepatitis B virus DNA level as cut-off value), two groups were compared. Prognostic factors for overall survival and recurrence-free survival were evaluated. Additionally, subgroup analysis was conducted in patients with high viral load to investigate prediction of postoperative antiviral therapy on the long-term prognosis. Results With a median follow-up of 49.1 months, patients with high viral load had lower median overall survival (78.3 months vs. 111.4 months, P < 0.001) and RFS (44.6 months vs. 94.8 months, P < 0.001) compared with those with low viral load. Multivariate analysis revealed that preoperative high viral load was an independent risk factor affecting both overall survival and recurrence-free survival (both P < 0.001). The subgroup analysis revealed that postoperative antiviral therapy independently improved recurrence-free survival for patients with high viral load ( P = 0.001). Conclusions Hepatitis B virus-related HCC patients with preoperative high viral load led to poorer overall and recurrence-free survival than those with low viral load after curative resection. To prevent postoperative recurrence, antiviral therapy should be initiated in those patients with hepatitis B virus DNA ≥ 10,000 copies/ml.