Objectives <p>Social determinants of health (SDOH) contributed to preventable health inequities. However, association between SDOH and mortality in populations with cardiovascular-kidney-metabolic (CKM) syndrome remain still unclear. This study aims to investigate this association and the influence of SDOH on life expectancy in CKM syndrome populations.</p> Study design <p>A cohort study using data from the 2001–2018 National Health and Nutrition Examination Survey (NHANES). Participants with incomplete data were excluded.</p> Methods <p>CKM stages 1–4 were considered as CKM syndrome according to American Heart Association’s suggestions. Ten measures of SDOH were assessed, and the combined score of SDOH were calculated as the sum of the weighted scores for each SDOH. Participants were then categorized into 3 groups according to SDOH tertiles. After adjustment for confounders, cox regression models were fitted to investigate the association between SDOH and all-cause mortality. Restricted cubic splines (RCS), subgroup analysis, and interaction analysis were also constructed.</p> Results <p>During a median follow-up of 7.33 years (IQR 4.17–10.58), a total of 10,040 participants with CKM syndrome were enrolled. The linear positive association between SDOH and the risk of all-cause mortality was observed. Results were consistent in subgroup analysis and several sensitivity analyses, and interaction analysis showed that this association can be modified by drinking. We also found that unfavorable SDOH correlated with shorter life expectancy compared to favorable SDOH.</p> Conclusion <p>Unfavorable SDOH associated with higher risk of all-cause mortality and shorter life expectancy in populations with CKM syndrome, addressing the importance of integrating SDOH into the management of CKM syndrome.</p> Clinical trial number <p>Not applicable.</p>