BACKGROUND: Given evidence on the cardiovascular disease (CVD) risk conferred by comorbidity risk factors, the American Heart Association (AHA) recently introduced a novel staging construct, named cardiovascular-kidney-metabolic (CKM) syndrome. This study examined the association of CKM syndrome stages with all-cause and cardiovascular mortality among US adults. METHODS: Data were from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 at baseline linked to the 2019 National Death Index records. For each participant, the CKM syndrome was classified into five stages: stage 0 (no CKM risk factors), 1 (excess or dysfunctional adiposity), 2 (metabolic risk factors and chronic kidney disease), 3 (subclinical CVD), or 4 (clinical CVD). The main outcomes were all-cause and cardiovascular mortality. RESULTS: Among 34,809 participants (mean age: 46.7 years; male: 49.2 %), the prevalence of CKM stages 0 to 4 was 13.2 %, 20.8 %, 53.1 %, 5.0 %, and 7.8 %, respectively. During a median follow-up of 8.3 years, compared to participants with CKM stage 0, those with higher stages had increased risks of all-cause mortality (stage 2: HR 1.43, 95 % 1.13-1.80; stage 3, HR 2.75, 95 % CI 2.12-3.57; stage 4, HR 3.02, 95 % CI 2.35-3.89). The corresponding hazard ratios (95 % confidence interval) of cardiovascular mortality risks were 2.96 (1.39-6.30), 7.60 (3.50-16.5), and 10.5 (5.01-22.2). The population-attributable fractions for advanced (stages 3 or 4) vs. CKM syndrome stages (stages 0, 1, or 2) were 25.3 % for all-cause mortality and 45.3 % for cardiovascular mortality. CONCLUSION: Higher CKM syndrome stages were associated with increased risks of all-cause and cardiovascular mortality. These findings emphasize that primordial and primary prevention efforts on promoting CKM health should be strengthened to reduce mortality risk.