Abstract Background Inflammatory markers are significantly associated with cardiovascular disease and many markers have been used as predictor in patients with STEMI. This study examines the predictive value of the novel systemic immune-inflammation index (SII) in patients with ST-segment elevation myocardial infarction (STEMI). Method A total of 1660 patients with STEMI who underwent primary percutaneous coronary intervention in a tertiary heart center were enrolled in the study. SII was calculated using the following formula: Platelet × Neutrophil/Lymphocyte ratio. The patients were stratified into four quartiles (Q) according to admission SII level. In-hospital and 3-year outcomes were compared between the four groups (Q1–4) Results In-hospital cardiogenic shock, acute respiratory failure, acute kidney injury, ventricular arrhythmia, stent thrombosis, recurrent myocardial infarction, major adverse cardiac events, and mortality were significantly higher in the high SII groups (Q3 and Q4). Logistic regression models demonstrated that Q3 and Q4 had independent risk of mortality and Q4 had an independent risk of cardiogenic shock compared to Q1. ROC analysis showed that the best cut-off value of the Systemic Immune-Inflammatory Index to predict the in-hospital mortality was 1781 with 66% sensitivity and 74% specificity (AUC: 0.75; 95% CI: 0.69–0.81; p<0.001). Kaplan Meier overall survivals for Q1, Q2, Q3 and Q4 were 97.6%, 96.9%, 91.6% and 81.0% respectively. Cox proportional analysis for 3-year mortality demonstrated that Q3 and Q4 had independent risk of death compared to Q1. Conclusion SII, a novel inflammatory index, had a better prediction of in-hospital and long-term outcomes than traditional risk factors in patients with STEMI. Funding Acknowledgement Type of funding sources: None.