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Background: The association between sleep-related disorders and inflammation has been demonstrated in previous studies. The systemic immune-inflammation index (SII) is a novel inflammatory index based on leukocytes, but its relationship with sleep-related disorder is unclear. We aimed to investigate the relationship between sleep-related disorder and SII in a nationally representative nonhospitalized sample., Methods: Data were obtained from the 2005-2008 National Health and Nutrition Examination Survey (NHANES). Exposure variables included self-reported sleep-related disorders, such as sleep duration, sleep problems, high risk of OSA, and daytime sleepiness. SII and other traditional markers of inflammation were considered as outcome variables, including platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR). Multiple linear regression models were employed to examine the correlation between sleep-related disorders and inflammatory markers. Subgroup interactions were analyzed using likelihood ratio tests, and nonlinear relationships were explored by fitting restricted cubic splines., Results: A total of 8,505 participants were enrolled in this study. Overall, sleep-related disorders were found to have a stronger association with SII compared to the PLR and NLR. The results of multiple linear regression analysis revealed that participants who experienced sleep problems (β: 21.421; 95% CI 1.484, 41.358), had symptoms of OSA (β: 23.088; 95% CI 0.441, 45.735), and reported daytime sleepiness (β: 30.320; 95% CI 5.851, 54.789) exhibited a positive association with higher SII. For the analysis of other inflammatory markers, we only found that daytime sleepiness was associated with increased NLR levels (β: 0.081; 95% CI 0.002, 0.159)., Conclusion: Sleep problems, symptoms of OSA, and daytime sleepiness were found to have a positive association with the SII in US adults. However, further prospective studies are necessary to establish whether there is a causal relationship between these factors., (© 2023. BioMed Central Ltd., part of Springer Nature.)