〔Abstract〕 Objective To investigate the methylation status of the RUNX family transcription factor 3(RUNX3) promoter and its mRNA expression in sepsis patients, and to analyze their relationship with the prognosis of sepsis. Methods Differentially expressed genes related to sepsis, including RUNX3, were identified from multiple datasets obtained from the gene expression omnibus(GEO) database. The gene expression and methylation sites were validated. A total of 120 patients with sepsis were included. Clinical data were recorded, and blood samples were collected at enrollment. Relative expression levels of RUNX3 in blood samples and promoter methylation status were detected using qPCR and methylation-specific PCR(MSP), respectively. Pearson correlation coefficients were used to analyze the correlation between RUNX3 levels in patient blood and clinical indicators. Kaplan-Meier analysis was performed to plot survival curves, and Cox proportional hazards regression analysis was conducted to identify factors affecting the prognosis of sepsis patients. Results Data set analysis revealed that RUNX3 was a differentially methylated gene associated with the prognosis of sepsis. The mRNA expression level of RUNX3 was lower in the non-survivor group compared to the survivor group(P