Background and aims: Hepatitis B virus (HBV) infection is a global health problem. The mechanisms of immune tolerance in HBV infection are still unclear. The host immune response plays a critical role in determining the outcome of HBV infection. Human leukocyte antigen-G (HLA-G) is involved in immunotolerogenic process and infectious diseases. The present study aimed to explore the implication of soluble HLA-G (sHLA-G) and its isoforms in HBV infection. Methods: Total sHLA-G (including shedding HLA-G1 and HLA-G5) was analysed by ELISA in 95 chronic HBV patients, 83 spontaneously resolvers and 100 healthy controls. To explore the presence of sHLA-G dimers, we performed an immunoprecipitation and a western blot analysis on positive samples for sHLA-G in ELISA. Results: The serum levels of sHLA-G were significantly increased in patients with chronic HBV patients compared to spontaneously resolvers and healthy controls (P<0.0001). Interstingly, we found an increased level of sHLA-G1 in chronic HBV patients than in spontaneously resolvers and healthy controls (P<0.001). In addition, the expression of HLA-G5, seems to be higher in the sera of chronic HBV patients then spontaneously resolvers (P=0.026). The analysis of HLA-G dimers showed the presence of homodimers in 93% of chronic HBV patients, 67% in spontaneously resolvers and 60% in healthy controls. Conclusion: These results provide that sHLA-G may have a crucial role in the outcome of HBV infection and could be proposed as a biomarker for infection outcome. Based on its tolerogenic function, HLA-G might be considered as a new promising immunotherapeutic approach to treat the chronic infection with HBV.