Introduction: Hepatitis B virus (HBV)-related liver cirrhosis (LC) complicated with severe sepsis (SS) leads to HBV-related acute-on-chronic liver failure (HBV-ACLF). Programmed cell death ligand-1 (PD-L1)-associated immunosuppression is involved in both LC and SS. This study aimed to examine the expression and clinical relevance of PD-L1 on peripheral CD14+ monocytes in sepsis-induced HBV-ACLF. Material and methods: PD-L1 expression on peripheral CD14+ monocytes among the healthy control (HC), LC and LC + SS groups was examined using flow cytometry analysis and compared. In the LC + SS group, an SS-induced ACLF subgroup was identified. LC + SS patients were followed up for 28 days. The correlations between monocytic PD-L1 expression and illness severity scores and the prognostic value of monocytic PD-L1 expression in SS-induced HBV-ACLF patients was examined. Results: There were 17, 30 and 70 participants in the HC, LC and LC + SS groups, respectively. The monocytic PD-L1 expression was higher in the LC group compared with the HC group and in the LC + SS group compared with the LC group. The monocytic PD-L1 expression was positively correlated with the illness severity scores in LC + SS patients and predicted 28-day mortality of SS-induced HBV-ACLF patients (n = 59). Conclusions: Severe sepsis exhibits a superimposed effect of monocytic PD-L1 up-regulation on the basis of liver cirrhosis, and monocytic PD-L1 expression predicts 28-day mortality of SS-induced HBV-ACLF.