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Objectives This study aims to explore the associations of the neutrophil-to-lymphocyte ratio (NLR) and the systemic inflammatory response index (SIRI) with all-cause mortality among adults with nasal colonisation of Staphylococcus aureus (S. aureus).Design A cross-sectional study.Setting The National Health and Nutrition Examination Survey (2001–2004).Participants A total of 10 600 adults aged 18 years or older were included in this study, of whom 2805 were colonised with nasal S. aureus.Primary and secondary outcome measures All-cause mortality was considered as primary outcomes. Survey-weighted Cox proportional hazards models were applied to evaluate the associations of NLR and SIRI with all-cause mortality after adjustment for confounders. Predictive performance was assessed using time-dependent receiver operating characteristic (ROC) curves, and survival differences were illustrated by Kaplan-Meier (K-M) analysis. Restricted cubic spline (RCS) models further examined potential non-linear associations.Results During a median follow-up of 197 months, 595 deaths occurred. The fully adjusted Cox model showed that elevated NLR (1.87 (1.32, 2.65), p<0.001) and SIRI (1.88 (1.43, 2.48), p<0.001) were significantly associated with increased all-cause mortality risk. These associations were consistent across subgroup analyses by sex, age, education, race, family poverty income ratio, smoking, drinking, diabetes, cancer and long-term care. K-M curves showed significantly lower survival rates in high NLR and SIRI groups (p<0.0001). RCS analysis revealed non-linear relationships between NLR and SIRI, with all-cause mortality (p>0.05).Conclusions Elevated NLR and SIRI levels are positively associated with higher all-cause mortality risk among adult individuals with nasal S. aureus colonisation.