Hepatitis B core antigen (HBcAg) reflects viral replication and is the target of T cells which can reflect the progression of liver disease. We aim to evaluate the relationship between Peginterferon alfa-2a (Peg-IFNα-2a) and the expression intensity of hepatitis B core antigen in chronic hepatitis B (CHB) patients in this study. 207 patients were enrolled with HBeAg-positive CHB and performed liver biopsy to determine the expression intensity of HBcAg detected by immunocytochemistry. All patients received 180μg of Peg-IFNα-2a once weekly for 48 weeks. We evaluated therapy response after 48 weeks of Peg-IFNα-2a therapy. All patients were divided into four groups (0 point group, 1 point group,2 point group,3 point group)by the expression intensity of HBcAg. Statistics on 207 patients, 118 (57.00%) had over 66% HBcAg expression (3 point group), 30 (14.49%) had 34%-66% HBcAg expression (2 point group), 45(21.74%) cases had 5%-33% HBcAg expression (1 point group), while only 14 (6.76%) had less than 5% HBcAg (0 point group). 0 point group has the lowest baseline HBV DNA among the four groups (P < 0.01). The degrees of baseline Liver tissue inflammation and fibrosis among the four groups have no difference(P > 0.05). The combination response was significantly higher in the 0 point group than in the 3 point group (57.1 % and 18.6 %, P < 0.01) after 48 weeks of Peg-IFNα-2a therapy. In conclusion, CHB patients at lower expression intensity of HBcAg have a better response to Peg-IFNα-2a therapy than at higher expression intensity of HBcAg.