Background <p>Systemic inflammation has been linked to increased mortality risk. However, the prognostic value of cumulative systemic inflammation response index (SIRI) remains unclear in individuals with cardiovascular-kidney-metabolic (CKM) syndrome stages 0–2.</p> Methods <p>Participants were enrolled from the Tongzhou cohort and underwent health examinations in 2016 and 2018. Cumulative SIRI was calculated as the time-weighted average of SIRI from two pre-follow-up examinations to reflect cumulative inflammatory burden before follow-up. Participants were categorized into high and low cumulative SIRI groups according to a cut-off determined by time-dependent receiver operating characteristic (ROC) analysis. Follow-up ended on December 31, 2024, with all-cause mortality as the primary outcome. Cox proportional hazards models and restricted cubic spline (RCS) analyses were applied to evaluate the association between cumulative SIRI and mortality risk.</p> Results <p>A total of 3,410 middle-aged and elderly participants with CKM syndrome stages 0–2 were enrolled. During a median follow-up of 74 months, 71 deaths (2.08%) occurred. After adjusting for confounders, high cumulative SIRI was associated with an increased risk of all-cause mortality (HR = 2.24, 95% CI: 1.01–4.97). Subgroup analyses revealed no significant interactions between cumulative SIRI and age, sex, marital status, education, smoking, or drinking status. RCS analysis showed a linear positive association between cumulative SIRI and all-cause mortality risk.</p> Conclusion <p>Higher cumulative SIRI was associated with increased risk of all-cause mortality in middle-aged and older adults with CKM syndrome stages 0–2. These findings suggest that cumulative SIRI, estimated from two pre-follow-up measurements, may have potential prognostic relevance, although further validation is needed.</p>