〔Abstract〕 Objective To analyze the correlation between the changes of serum endothelial cell-specific molecule-1 (ESM- 1) and micro ribonucleic acid-155-5p (miR-155-5p) levels and the prognosis of patients with sepsis. Methods A total of 122 patients with sepsis admitted to the First Affiliated Hospital of Fujian Medical University from April 2019 to February 2021 were selected and divided into three groups according to the severity of their disease: ordinary sepsis group with 52 cases, severe sepsis group with 39 cases and septic shock group with 31 cases; Another 30 healthy subjects who underwent physical examination during the same period were selected as the control group. Fasting venous blood was taken from all groups, serum ESM-1 level was detected by enzyme-linked immunosorbent assay (ELISA), and the miR-155-5p level was detected by reverse transcription polymerase chain reaction (RT-PCR). Moreover, serum ESM-1, miR-155-5p and sequential organ failure assessment (SOFA) of the four groups were compared, the serum levels of ESM-1 and miR-155-5p in sepsis patients with different SOFA were compared, and their correlation was analyzed. Results There were statistically significant differences in serum ESM-1, miR-155-5p and SOFA among the four groups (P < 0.05), and the order of levels among the four groups was septic shock group > severe sepsis group > normal sepsis group > control group. Statistically significant differences could be observed in the comparison of serum ESM-1 and miR-155-5p in sepsis patients with different SOFA (P < 0.05), and the higher SOFA was, the higher serum ESM-1 and miR-155-5p levels were. SOFA was positively correlated with serum ESM-1 and miR-155-5p in patients with sepsis. Conclusion Increased levels of ESM-1 can promote the accumulation of chemokines and increase vascular endothelial damage, while high-level expression of miR-155-5p can induce immune imbalance and lead to abnormal redox reactions, both of which are closely related to the prognosis of patients with sepsis, and a high level of expression indicates more severe disease in patients.