Objective: To investigate the expression level of Toll-like receptor 4 (TLR-4) on peripheral blood mononuclear cell (PBMC) surface, levels of serum C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and procalcitonin (PCT) and their clinical significance in patients with severe pneumonia complicated with sepsis. Methods: The clinical data of 104 patients with severe pneumonia complicated with sepsis and 32 patients with severe pneumonia but without sepsis (the control group) in our hospital were retrospectively analyzed. The patients with sepsis were divided into a severe sepsis group (the severe group) and a non-severe sepsis group (the non-severe group) according to the disease severity. The baseline data and differences in expression level of PBMC surface TLR-4, levels of serum CRP, TNF-α and PCT at 24 h after admission were compared among the three groups, and the receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of expression level of peripheral venous blood PBMC surface TLR-4, serum CRP, TNF-α and PCT at 24 h after admission and their combined detection on severe pneumonia with severe sepsis, and the mortality rate at 28 d after admission was recorded among the three groups. Results: There were no significant differences in the gender, smoking history and concurrent rates of bronchiectasis, bronchial asthma and hypertension among the three groups (P>0.05). But the age and concurrent rates of chronic obstructive pulmonary obstruction and diabetes mellitus in severe group were higher than those in non-severe group and those in control group (P<0.05), and the age in non-severe group was higher than that in control group (P<0.05). Comparison of expression level of peripheral venous blood PBMC surface TLR-4 and levels of serum CRP, TNF-α and PCT in the three groups at 24 h after admission showed that the severe group > the non-severe group > the control group (P<0.05). After ROC curve analysis, it was found that expression level of peripheral venous blood PBMC surface TLR-4 and serum CRP, TNF-α and PCT at 24 h after admission had high diagnostic value on severe pneumonia with severe sepsis (P<0.05), and the combined detection of the four had the highest diagnostic value. Comparison of mortality rate of the three groups at 28 d after admission showed that the severe group > the non-severe group > the control group (P<0.05). Conclusion: The expression level of peripheral venous blood PBMC surface TLR-4 and levels of serum CRP, TNF-α and PCT of patients with severe pneumonia complicated with sepsis can be significantly increased in the early stage of admission, and the combined detection of the above indexes has a higher diagnostic value on severe sepsis, and TLR-4 signaling pathway may be an important way to cause strong systemic inflammatory response, and is expected to become a new direction for the diagnosis and treatment of severe pneumonia with sepsis.