Purpose: To examine the biological behavior and effects of ILT4 on monocytes in sepsis and explore the corresponding molecular regulatory mechanism. Materials and Methods: ILT4+/+ (WT) and ILT4-knockout mice (ILT4−/−) male BALB/c mice were used for sepsis modeling using CLP. Flow cytometry was used to measure the levels of expression of ILT4 and MHC-II on monocytes. ELISA was used to measure the concentrations of serum TNF-α, IL-1β, IL-6, and IL-12. And exogenous IL-6 and anti-IL-6 mAb are used to control the biological activity and concentration of serum IL-6 to observe the centering effect of IL-6. Results: ILT4 was highly expressed on monocytes 24 h after CLP (p<0.05). MHC-II expression on monocytes of ILT4−/− mice was significantly higher than in WT mice (p<0.05). And the survival of ILT4−/− mice was significantly better after CLP compared than in WT mice. Serum IL-6 was significantly elevated 24 h after CLP (p<0.05), which was significantly suppressed after ILT4 ablation (p<0.05). Subcutaneously injection with exogenous IL-6 made the monocytes of the ILT4−/− mice after CLP to maintain low proportion of MHC-II-expressing monocytes. Conclusions: ILT4–IL-6–MHC-II is involved in the biological regulatory mechanism by which monocytes functionally dissimilation in sepsis.