〔Abstract〕 Objective To study the efficacy and safety of peginterferon α-2a (PEG) combined with Entecavir (ENT) in the treatment of chronic hepatitis B. Methods 100 patients with chronic hepatitis B admitted to the Jianli People's Hospital from January 2020 to January 2021 were selected as research objects. According to treatment methods, they were divided into ENT group and PEG+ENT group, with 50 cases each. The differences of efficacy, adverse reactions, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBIL), CD3+ , CD4+ and CD8+ cells between the two groups were compared. Results The treatment effective rate, hepatitis B virus deoxyribonucleic acid (HBV-DNA) negative conversion rate and hepatitis Be antigen (HBeAg) negative conversion rate in PEG+ENT group were significantly higher than those in ENT group, the differences were statistically significant (P < 0.05). The incidence of bone marrow depression, liver and kidney function damage, gastrointestinal symptoms and rash in PEG+ENT group was higher than that in ENT group. ALT, AST, TBIL, CD3+ , CD4+ and CD8+ were significantly decreased in ENT group and PEG+ENT group after treatment, with statistical significance (P < 0.05). ALT, AST and TBIL of PEG+ENT group were significantly lower than those of ENT group, while CD3+ , CD4+ and CD8+ were significantly higher than those of ENT group, the difference was statistically significant (P < 0.05). Conclusion The curative effect of PEG combined with ENT in the treatment of chronic hepatitis B is significantly higher than that of ENT, which can significantly improve liver function and immune function, and has the advantages of high efficiency and safety.