Interleukin-21 (IL-21) participates in tissue damage in various immune-mediated diseases. Its role in the pathogenesis of chronic active hepatitis B (CAHB) has not been clarified. The frequency of circulating IL-21(+) T cells and the levels of serum and intrahepatic IL-21 have been characterized in 70 CAHB patients, 32 inactive carrier (IC), 18 chronic hepatitis C (CHC) and 20 healthy controls (HC). Their potential association with liver injury was analysed. The percentages of IL-21(+) CD3(+) CD8(-) and IL-21(+) CD3(+) CD8(+) T cells and the levels of serum IL-21 in CAHB patients were significantly higher than that in the IC, CHC patients and HC (P < 0.001) and were correlated positively with the levels of serum alanine aminotransferase (ALT, r = 0.424, P < 0.001; r = 0.392, P = 0.001) and aspartate aminotransferase (AST, r = 0.388, P = 0.001; r = 0.329, P = 0.005) in CAHB patients, respectively. The levels of IL-21 expression in the liver tissues were associated significantly with increased degrees of inflammation and fibrosis in CAHB patients (P < 0.01 or P < 0.05). Our findings suggest that aberrant IL-21 responses may be associated with the progression of CHB.