Background <p>The systemic immune inflammatory index (SII) is an emerging inflammatory marker and the effectiveness of air enema treatment may correlate with the degree of intestinal inflammation caused by ileocolic intussusception (ICI). Our goal was to identify the SII as a predictor of air enema failure, so that pediatric surgeons can perform surgical intervention in children with ICI as soon as possible, to minimize complications.</p> Methods <p>This single-center, retrospective, case-control study was conducted on children with ileocolic intussusception between 2017 and 2024. The admission demographic, clinical, and laboratory data were analyzed. The specificity and sensitivity of various parameters as predictors of the failure of air enema treatment were established using receiver operating characteristic (ROC) curves.</p> Results <p>A total of 574 patients were included in the study (469 in the air enema success group and 105 in the air enema failure group). There was an independent positive correlation between SII and the risk of air enema treatment failure in ICI. Additionally, a nonlinear dose–response relationship was observed between SII and air enema treatment failure in ICI within the RCS. Threshold analysis revealed that on the right of this inflection point 332.3, there was a significant 25% increase in the prevalence of air enema treatment failure risk of ICI per 100-unit increase in the SII (OR: 1.25, 95%CI: 1.17–1.32). In the ROC curve analysis, SII demonstrated the highest area under the curve (AUC) of 0.8665 (95%CI: 0.8313–0.9018) compared to other inflammation indices. The critical point for SII was estimated to be 721.5 (sensitivity, 86.67%; specificity, 71.00%).</p> Conclusions <p>The SII, a novel, cost-effective, and objective inflammatory marker, can be utilized to predict the risk of air enema treatment failure in children with ileocolic intussusception.</p>