Purpose: There have been limited studies examining the prospective association between the Systemic Immune-Inflammation Index (SII), a novel inflammatory marker, and mortality among individuals with diabetes in the United States.Methods: We utilized data from the National Health and Nutrition Examination Survey (NHANES), a representative sample of US adults, linked with information from the National Death Index.Results: Our study included 8697 individuals from NHANES spanning the years 1999 to 2018. SII was calculated by dividing the platelet count by the neutrophil count and then dividing that result by the lymphocyte count. We employed multivariable Cox proportional hazards regression analysis to investigate the associations between SII levels and all-cause as well as cause-specific mortality, while adjusting for potential confounding factors. SII levels were categorized into quartiles based on the study population distribution. Over a median follow-up period of 94.8 months (with a maximum of 249 months), we observed a total of 2465 all-cause deaths, 853 deaths from cardiovascular causes, 424 deaths from cancer, and 88 deaths related to chronic kidney disease. After adjusting for multiple variables, higher SII levels were significantly and non-linearly associated with an increased risk of all-cause mortality in Quartile 4 (HR 1.74, 95% CI 1.15–2.63, P for trend = 0.043) when Quartile 1 was used as the reference group. Additionally, we identified a linear association between SII and cardiovascular mortality, with a 70% higher risk of cardiovascular mortality in Quartile 4 (HR 1.70, 95% CI 1.18–3.30, P for trend = 0.041) compared to Quartile 1.Conclusion: Our findings indicate that SII is significantly associated with an elevated risk of all-cause and cardiovascular mortality in US adults with diabetes.