〔Abstract〕 Objective To compare the antiviral efficacy and renal safety of nucleoside analogs(NAs) monotherapy versus combination therapy in hepatitis B e antigen(HBeAg)-positive chronic hepatitis B(CHB) patients with high viral load. Methods This study enrolled a total of 353 treatment-na6ve HBeAg-positive chronic hepatitis B(CHB) patients with high viral load, the treatment regimen was divided into 5 groups, consisting of 4 monotherapy groups and 1 combination therapy group as follows: 88 cases in the Entecavir(ETV) group, 135 cases in the Tenofovir Disoproxil Fumarate(TDF) group, 34 cases in the Tenofovir Alafenamide Fumarate(TAF) group, 25 cases in the Tenofovir Amibufenamide(TMF) group, and 71 cases in the ETV combined with TDF(ETV+TDF) group. A retrospective cohort study design was adopted to analyze HBV DNA levels, serological indicators(HBsAg and HBeAg levels), renal function indicators(serum Scr levels, eGFR) at 24 and 48 weeks of treatment across various groups, as well as the HBsAg clearance rates, HBeAg seroconversion rates and HBV DNA suppression rates(HBV DNA0.05). At 48 weeks, the HBV DNA levels in the ETV+TDF combination therapy group was significantly lower than those in all monotherapy groups(P0.05). The HBV DNA level in the ETV group was higher than those in the remaining four groups(P0.05). Conclusion For HBeAg-positive chronic hepatitis B(CHB) patients with high viral load, the combination therapy of ETV and TDF significantly enhances viral suppression compared to monotherapy, without increasing the risk of renal adverse events. This suggests that the combination therapy can be considered a preferred strategy for this specific patient population.