Objective: To analyze the factors affecting the efficacy of ?-interferon in the treatment of chronic hepatitis B (CHB). Methods: A total of 100 patients with CHB treated in our hospital from June 2018 to June 2019 were selected. All patients were treated with ?-interferon to evaluate the efficacy, and the factors affecting the effect of ?-interferon on CHB were analyzed. Results: After treatment, 54 patients fully responded and 46 patients did not; the levels of white blood cells, HBV DNA, and HBsAg in the complete response group were lower than those in the incompletely response group, and the differences were statistically significant (P <0.05); Multivariate logistic regression analysis found that serum HBV DNA and HBsAg were independent factors affecting the efficacy of ?-interferon in the treatment of CHB (OR> 1, P<0.05). Conclusion: Serum HBV DNA and HBsAg are risk factors that affect the efficacy of ?-interferon in the treatment of CHB. Monitoring the changes of serum HBV DNA and HBsAg levels has important clinical significance for predicting the efficacy.