Hepatocellular carcinoma (HCC) is a global health burden and hepatitis B virus (HBV) infection is a common cause. Antiviral therapy has the possibility to reduce the incidence of HCC, and recurrence of HCC after surgical resection.

A total of 410 HCC patients had hepatectomy at Zhongnan hospital of Wuhan University. Categorization of these patients was done on the basis of HBV antiviral therapy. Recurrence-free survival (RFS) and the overall survival (OS) rates were assessed during follow-up period. Tumor necrosis percentage, recovery of liver functions, and tumor-related characteristics were also examined in these patients. Statistical analyses were conducted using Kaplan–Meier survival curves and Cox regression models.

After applying strict selection criteria, only 93 patients formed the observation group. These patients had comparatively smaller tumor size ≤5 cm(76.3% vs. 45.1%) and less tumor necrosis (30.1% vs. 54.6%). OS (p = 0.035) and RFS (p = 0.034) was also improved in the observation group. However, antiviral therapy did not show any significant effect on OS (p = 0.188) and RFS (p = 0.527) after a multivariate adjustment. Microvascular invasion of more than 5 foci (OS HR = 2.96; RFS HR = 1.97), poor differentiation (RFS HR = 2.70), and stage C versus 0 of BCLC (OS HR = 3.75; RFS HR = 4.40) were independent adverse prognostic factors. Kaplan–Meier analysis indicated that tumour necrosis was associated with overall survival (OS) and recurrence-free survival (RFS), and this finding was validated in sensitivity analyses.

While antiviral therapy correlated with improved tumor pathology and univariate survival outcomes, it was not an independent prognostic factor after adjustment. Tumor necrosis independently predicted worse OS and RFS. Prognosis was primarily driven by microvascular invasion, poor differentiation, and advanced BCLC stage, suggesting antiviral benefits may operate indirectly through tumor biology modulation.