Abstract: Objective To investigate the clinical effectiveness of entecavir (ETV) or tenofovir (TDF) combined with pegylated interferon α-2b (PEG-IFNα-2b) in the treatment of patients with chronic hepatitis B (CHB).Methods A total of 107 CHB patients who were admitted to Department of Infectious Diseases, the Affiliated Hospital of Xuzhou Medical University from January 2019 to January 2022 were enrolled and their clinical data were retrospectively analyzed. Among them, 57 patients were treated with ETV combined with PEG-IFNα-2b, which was set as an ETV group, while 50 patients were administered with TDF combined with PEG-IFNα-2b, which was set as a TDF group. After treatment, the two groups were compared for serum alanine aminotransferase (ALT), hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg), as well as the negative conversion rate of serum HBsAg and HBeAg. After treatment, the HBsAg negative conversion group (n=33) and the non-negative conversion group (n=74) were compared for the differences of hepatitis B virus (HBV) antigen, liver function and blood routine indexes. Multivariate logistic regression analysis was conducted to evaluate the independent influencing factors of HBsAg negative conversion.Results There was no statistical difference in baseline data between the ETV and TDF groups (P>0.05). The differences in median serum ALT, HBsAg and HBeAg levels at 12, 24, 36 and 48 weeks of treatment and 24 weeks after treatment were not statistically significant (all P>0.05). The differences in serum HBsAg and HBeAg negative conversion rates at 24 and 48 weeks of treatment and 24 weeks after treatment were not statistically significant (all P>0.05). After treatment, the two groups showed a decreasing trend in the median serum HBsAg and HBeAg levels as a whole, while their median serum ALT levels were elevated at 12 weeks of treatment and then declined, compared with the baseline data. Baseline HBeAg status and HBsAg level, HBsAg level at 12 weeks of treatment, the ratio of HBsAg level at 12 weeks of treatment/baseline HBsAg and baseline WBC level were the independent influencing factors for HBsAg negative conversion.Conclusions ETV or TDF in combination with PEG-IFNα-2b has similar clinical effectiveness for the treatment of PEG-IFNα-2b. After treatment, CHB patients with negative baseline HBeAg, low baseline HBsAg level, low HBsAg level at 12 weeks of treatment, a low ratio of HBsAg level at 12 weeks of treatment/baseline HBsAg, or high baseline WBC level show a higher HBsAg negative conversion rate.