Human leukocyte antigen-G is involved in immunotolerogenic, inflammatory and carcinogenic process. This study investigated serum soluble HLA-G (sHLA-G) levels in patients with chronic hepatitis B virus (HBV) infection according to the infection phases and clinical diagnoses. The study included 223 patients with chronic HBV infection [phases: 38 immune-tolerant (IT), 83 immune clearance (IC), 30 non/low-replicative (LR) and 72 HBeAg negative hepatitis (ENH); diagnoses: 38 asymptomatic HBV carriers (ASC), 98 chronic hepatitis (CH), 46 cirrhosis (LC) and 41 hepatocellular carcinoma (HCC)], 62 HBV infection resolvers and 66 healthy controls. The sHLA-G levels in patients were elevated compared with resolvers and healthy controls (P < 0.001). According to phases, sHLA-G levels were higher in IC and ENH than in IT (P = 0.017 and P = 0.001, respectively). Serum sHLA-G levels were also higher in ENH than in LR (P = 0.008). According to diagnoses, sHLA-G levels in HCC were significantly increased compared with LC, CH and ASC (P = 0.010, P < 0.001 and P < 0.001, respectively). Serum sHLA-G levels were higher in CH than in ASC (P = 0.039). The sHLA-G levels in IC, ENH and CH were correlated with alanine aminotransferase levels (P = 0.011, P = 0.010 and P < 0.001, respectively). It is concluded that sHLA-G is involved in the pathogenesis of chronic HBV infection and correlates with infection phases and clinical diseases, suggesting the value in evaluating disease activity and defining clinical diagnosis.