OBJECTIVE: Evidence indicates that the systemic immune-inflammation index (SII) correlates with poor prognosis in various solid tumors. This retrospective study aimed to evaluate the diagnostic and prognostic significance of preoperative SII combined with tumor markers for early detection and prognosis of gallbladder cancer (GBC). METHODS: Preoperative SII levels and serum tumor markers [carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125), and carbohydrate antigen 19 - 9 (CA19-9)] were measured in GBC patients. Correlations and diagnostic efficacy were analyzed using Spearman correlation and receiver operating characteristic (ROC) curve analyses. The relationship between SII and clinical data was analyzed, and cumulative survival rates of the two groups were compared. Independent risk factors for poor prognosis in GBC patients were assessed using Kaplan-Meier curves and Cox multivariate analysis. RESULTS: Preoperative SII, CEA, CA125, and CA19-9 levels were significantly elevated in GBC patients compared to those with benign lesions. SII positively correlated with CEA, CA125, and CA19-9 levels (r = 0.434, 0.570, 0.614, respectively, all P <
0.001). The area under the ROC curve (AUC) for the combination of SII, CEA, CA125, and CA19-9 was 0.877 for early GBC diagnosis and 0.923 for predicting postoperative mortality, outperforming each marker individually. An SII threshold >
889.52 was predictive of postoperative death. High SII was associated with tumor size, differentiation, tumor-node-metastasis stage, lymph node metastasis, perineural invasion, surgical type, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and serum tumor marker levels. Kaplan-Meier analysis revealed poorer survival in the high SII group. Preoperative SII was identified as an IRF for poor prognosis in GBC patients. CONCLUSION: Preoperative SII correlates strongly with CEA, CA125, and CA19-9 levels. The combined use of SII and tumor markers offers high diagnostic value for early GBC detection and robust predictive value for postoperative mortality. Preoperative SII serves as an IRF for poor prognosis in GBC patients.