IL-37 is a new anti-inflammatory cytokine that plays an important role in protecting against tissue injury during infections via limiting immune and inflammatory reactions. This study aimed at determining serum IL-37 concentrations and HBeAg seroconversion in chronic hepatitis B virus (HBV) patients during Telbivudine (LDT) treatment. The serum levels of IL-37 were determined using enzyme-linked immunosorbent assay (ELISA) in 40 chronic hepatitis B virus infection (CHB) patients (HBeAg positive), 30 chronic hepatitis C virus infection (CHC) patients [25 with spontaneously resolved hepatitis C virus (SR-CHC)], and 30 healthy controls (HCs). Anti-inflammatory cytokines such as IL-2 and IL-10 were measured using cytometric bead array, and the concentrations of clinical parameters such as serum hepatitis B surface antigen (HBsAg), hepatitis B nucleocapsid antigen (HBeAg), alanine transaminase (ALT), aspartate transaminase (AST), HBV DNA, and hepatitis C virus (HCV) RNA loads were measured. It was found that the serum levels of IL-37 were higher in chronic HBV patients with high virus loads, but the association was not statistically significant. The serum levels of IL-37 were decreased in HBeAg seroconverted CHB patients after 48 weeks of LDT treatment. The serum levels of IL-37 had no significant difference in CHC patients compared with SR-HCV and HCs. The levels of anti-inflammatory cytokine, IL-2 and IL-10, were lower in CHB and CHC patients than the HC, but IL-2 levels increased after LDT treatment in CHB patients. The concentrations of serum IL-37 in CHB and CHC patients with abnormal levels of serum ALT (>50 U/L) or AST (>40 U/L) were significantly higher than CHB, CHC patients with normal levels of ALT (<50 U/L) or AST (<40 U/L). These results suggest that IL-37 may play a significant role in the immune response of CHB patients with HBeAg seroconversion. The serum levels of IL-37 are associated with liver damage in CHB patients.