摘要Due to the low specificity and sensitivity of biomarkers in sepsis diagnostics, the prognosis of sepsis patient outcomes still relies on the assessment of clinical symptoms. Inflammatory response is crucial to sepsis onset and progression; however, the significance of inflammatory response-related genes (IRRGs) in sepsis prognosis is uncertain. This study developed an IRRG-based signature for sepsis prognosis and immunological function. The Gene Expression Omnibus (GEO) database was retrieved for two sepsis microarray datasets, GSE64457 and GSE69528, followed by gene set enrichment analysis (GSEA) comparing sepsis and healthy samples. A predictive signature for IRRGs was created using least absolute shrinkage and selection operator (LASSO). To confirm the efficacy and reliability of the new prognostic signature, Cox regression, Kaplan-Meier (K-M) survival, and receiver operating characteristic (ROC) curve analyses were performed. Subsequently, we employed the GSE95233 dataset to independently validate the prognostic signature. A single-sample GSEA (ssGSEA) was conducted to quantify the immune cell enrichment score and immune-related pathway activity. We found that more gene sets were enriched in the inflammatory response in sepsis patient samples than in healthy patient samples, as determined by GSEA. The signature of nine IRRGs permitted the patients to be classified into two risk categories. Patients in the low-risk group showed significantly better 28-d survival than those in the high-risk group. ROC curve analysis corroborated the predictive capacity of the signature, with the area under the curve (AUC) for 28-d survival reaching 0.866. Meanwhile, the ssGSEA showed that the two risk groups had different immune states. The validation set and external dataset showed that the signature was clinically predictive. In conclusion, a signature consisting of nine IRRGs can be utilized to predict prognosis and influence the immunological status of sepsis patients. Thus, intervention based on these IRRGs may become a therapeutic option in the future.