OBJECTIVES: The American Heart Association defined cardiovascular-kidney-metabolic (CKM) syndrome as a novel multi-stage disorder. We examined the associations of CKM stages with premature mortality and the role of social determinants of health (SDOHs). DESIGN: A prospective cohort study. SETTING AND PARTICIPANTS: A nationally representative sample of US adults from NHANES 1999-2018. MEASUREMENTS: CKM included 5 stages (stages 0-4), reflecting progressive pathophysiology. Premature mortality (deaths before 75 years) were ascertained via linkage to the National Death Index with follow-up until 2019. Cox proportional-hazards models adjusted for age, sex, race/ethnicity, medical history, and other confounding factors were used to calculate the hazard ratios (HR) and 95% CIs for CKM-mortality associations. RESULTS: Among 27,909 participants (mean age 49.7 years, 49.0% females), 1762 premature deaths occurred over a median follow-up of 8.3 years. Compared with stage 0, the adjusted HRs for all-cause premature mortality at CKM stages 1-4 were 0.88 (95% CI 0.66-1.17), 1.31 (0.99-1.73), 1.94 (1.31-2.87), and 2.19 (1.61-2.98), respectively. For CVD premature mortality, the adjusted HRs for CKM stages 1-4 were 1.12 (0.46-2.72), 1.74 (0.71-4.28), 3.93 (1.53-10.12), and 6.48 (2.95-14.20), respectively. Among adults at CKM stages 3-4, unfavorable SDOHs, particularly not living with a partner, low family income, lack of private health insurance, unemployment, or ≥2 cumulative SDOHs (4.16, 95% CI 3.35-5.18) were associated with increased all-cause premature mortality. Among those at CKM stages 0-2, unfavorable SDOHs were also related to increased premature mortality. CONCLUSION: CKM stages 3-4, but not stages 1-2, were associated with increased risks of premature mortality compared with stage 0. The risks were increased by unfavorable SDOHs across CKM stages.