Objective To observe the efficacy of entecavir （ETV） alone and in combination with peginterferon （Peg-IFN） in the treatment of patients with high viral load chronic hepatitis B （CHB）. Methods This prospective cohort study included 152 patients with high viral load CHB who were treated at four hospitals， including the First Affiliated Hospital of Nanchang University， between December 2019 and December 2023. Based on the patients' conditions and their own wishes， the patients were divided into the ETV group （n = 102） and the Peg-IFN and ETV combined treatment group （n = 50）. The primary endpoint was defined as HBV surface antigen （HBsAg） seroclearance at week 48. Secondary endpoints were the 48-week HBsAg decline level， HBV e antigen （HBeAg） seroclearance， HBV-DNA negative conversion rate and decline level， and ALT decline level. Measurement data conformed to normal distribution and were compared between two groups using two independent samples t-test， and within-group comparisons before and after treatment were analyzed using repeated measures ANOVA. Count data were compared between two groups using the chi-square test， and within-group comparisons before and after treatment were statistically analyzed using Cochran's Q test for multiple comparisons. Results ALT， HBV-DNA， and HBsAg levels decreased significantly in both groups throughout the 48-week treatment period compared with pre-treatment （P < 0.001）. At 48 weeks of treatment， alanine aminotransferase （30.82 ± 9.86） U/L was significantly lower in the ETV group than in the combination therapy group （37.57 ± 19.84） U/L （P = 0.027）； The HBV-DNA and HBsAg levels in the ETV group were significantly higher at（1.22 ± 1.17）lg IU/mL and（3.65 ± 0.85）lg IU/mL， respectively， than those in the combination therapy group at（0.82 ± 0.96）lg IU/mL and（2.62 ± 1.45）lg IU/mL （P = 0.034， P < 0.001）. Both HBeAg and HBV-DNA clearance were significantly higher in the ETV group at 48 weeks of treatment compared with pre-treatment （P < 0.001）， whereas the difference between HBsAg clearance and pre-treatment was not statistically significant （P = 0.171）. HBsAg， HBeAg， and HBV-DNA clearance rates were significantly higher in the combination therapy group at 48 weeks of treatment compared to pre-treatment （P < 0.05）. At 48 weeks of treatment， HBsAg and HBeAg seroclearance rates of 2.0% and 13.7%， respectively， were significantly lower in the ETV group than in the combination therapy group at 12.0% and 38.0% （P = 0.027， P = 0.001）； The HBV-DNA clearance rate of 89.2% in the ETV group was lower than that of 94.0% in the combination therapy group， but the difference was not statistically significant （P = 0.509）. Conclusion The Peg-IFN combined with ETV regimen can be the first recommended treatment option for patients with high viral load CHB.