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BackgroundInflammation has been linked to the development of coronary heart disease (CHD). The systemic immune inflammation index (SII) is a useful biomarker of systemic inflammation. Our study aimed to explore the correlation between SII and CHD.MethodsWe conducted a multivariate logistic regression analysis, smoothing curve fitting, and segmented model comparison on 15,905 participants with a CHD prevalence of 3.31% and a mean age of 46.97 years.ResultsAdjusting for gender, age, and race, we found a negative association between SII and CHD [odds ratio (OR) 0.66; 95% confidence interval (CI) 0.48, 0.90]. There was an inverse trend where increasing SII was associated with decreasing odds of CHD (p for trend = 0.0017). After further adjustment, the association was strengthened, with a similar trend (p for trend = 0.0639). Smoothing curve fitting demonstrated a gender-specific association between SII and CHD.ConclusionsOur findings suggest that higher SII values may be associated with a higher incidence of CHD, which varies by gender. SII may be a cost-effective and convenient method to detect CHD. Further studies are needed to confirm the causality of these findings in a larger prospective cohort.