This study investigates the prognostic implications of the systemic immune-inflammation index (SII) in patients with and without diabetes following acute myocardial infarction (AMI). The SII, calculated as the product of platelet count and neutrophil-to-lymphocyte ratio, is a novel biomarker used to assess systemic inflammation. The study included 2111 AMI patients from the NOAFCAMI-SH registry, with 789 (37.4%) having diabetes. Multivariable Cox regression analyses were performed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cardiovascular (CV) death. The results showed that a higher log-transformed SII was significantly associated with increased all-cause mortality (HR: 1.57, 95%CI: 1.02–2.43) and CV mortality (HR: 1.85, 95%CI: 1.12–3.05), with these associations being more pronounced in diabetic patients (HRs for all-cause and CV death: 2.90 [1.40–6.01] and 3.28 [1.43–7.57], respectively). Additionally, restricted cubic spline analyses indicated a linear association between SII and mortality only in diabetic patients. The study concludes that high SII is an independent predictor of poor survival in AMI patients with diabetes, suggesting its potential utility in risk stratification and clinical decision-making.This study investigates the prognostic implications of the systemic immune-inflammation index (SII) in patients with and without diabetes following acute myocardial infarction (AMI). The SII, calculated as the product of platelet count and neutrophil-to-lymphocyte ratio, is a novel biomarker used to assess systemic inflammation. The study included 2111 AMI patients from the NOAFCAMI-SH registry, with 789 (37.4%) having diabetes. Multivariable Cox regression analyses were performed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cardiovascular (CV) death. The results showed that a higher log-transformed SII was significantly associated with increased all-cause mortality (HR: 1.57, 95%CI: 1.02–2.43) and CV mortality (HR: 1.85, 95%CI: 1.12–3.05), with these associations being more pronounced in diabetic patients (HRs for all-cause and CV death: 2.90 [1.40–6.01] and 3.28 [1.43–7.57], respectively). Additionally, restricted cubic spline analyses indicated a linear association between SII and mortality only in diabetic patients. The study concludes that high SII is an independent predictor of poor survival in AMI patients with diabetes, suggesting its potential utility in risk stratification and clinical decision-making.