Objective:To analyze the plasma levels of soluble immune checkpoint molecules in patients with primary liver cancer and their prognostic significance.Methods:The levels of sCD28, sCD80, sCD137, sCD27, sGITR, sTIM3, sCTLA4, sHVEM, IDO, sLAG3, sBTLA, sPD1, sPDL1 and sPDL2 in plasma samples of 58 patients with primary liver cancer and 30 healthy controls were detected by liquid chip technology and compared between different groups. The relationship between the plasma levels of soluble immune checkpoint molecules and tumor recurrence was analyzed.Results:The levels of sCD28 and sCD80 were higher in patients in Barcelona Clinic Liver Cancer (BCLC) stage 0/A and B than in healthy controls and patients in BCLC-C stage ( P<0.05). However, the levels of sCD27 and sHVEM in BCLC-C patients were significantly lower than those in BCLC-0/A and BCLC-B patients, and even lower than healthy control group. The levels of sCD137, IDO and sPD1 in BCLC-0/A and BCLC-B patients were higher than those in healthy controls. The levels of sPDL1 and sPDL2 in different BCLC stages were all higher than those in healthy controls, and maintained at high level in the three stages, but there was no significant difference between different stages. After 24 months of interventional treatment, the preoperative sCD28 level was lower in patients with recurrent tumor recurrence than in patients without recurrence ( t=2.843, P=0.007). The optimal cut-off value of sCD28 based on the receiver operating characteristic (ROC) curve for predicting tumor recurrence was 101.42 pg/ml and the area under the ROC curve was 0.771 (95%CI: 0.611-0.931) with a sensitivity of 0.889 and a specificity of 0.666. The cumulative recurrence rate in patients with high sCD28 level (≥101.41 pg/ml) was 57.9% at 24 months after surgery, which was lower than the rate (95.5%) in patients with low sCD28 level (<101.41 pg/ml). The difference in the cumulative recurrence rate between the two groups was statistically significant (χ 2=15.777, P=0.000). Conclusions:The expression patterns of soluble immune checkpoint molecules varied in patients at different stages of primary liver cancer, suggesting that there were differences in their immune status and sCD28 could be used as a prognostic marker for postoperative recurrence of liver cancer.