ObjectiveTo validate a Cardiometabolic Disease Staging (CMDS) system for assigning risk level for diabetes, and all‐cause and cardiovascular disease (CVD) mortality.Design and MethodsTwo large national cohorts, CARDIA and NHANES III, were used to validate CMDS. CMDS: Stage 0: metabolically healthy; Stage 1: one or two metabolic syndrome risk factors [other than impaired fasting glucose (IFG)]; Stage 2: IFG or impaired glucose tolerance (IGT) or metabolic syndrome (without IFG); Stage 3: two of three (IFG, IGT, and/or metabolic syndrome); and Stage 4: type 2 diabetes mellitus/CVD.ResultsIn the CARDIA study, compared with Stage 0 metabolically healthy subjects, adjusted risk for diabetes exponentially increased from Stage 1 [hazard ratio (HR) 2.83, 95% confidence interval (CI): 1.76‐4.55], to Stage 2 (HR 8.06, 95% CI 4.91‐13.2), to Stage 3 (HR 23.5, 95% CI 13.7‐40.1) (P for trend <0.001). In NHANES III, both cumulative incidence and multivariable adjusted HRs markedly increased for both all‐cause and CVD mortality with advancement of the risk stage from Stages 0 to 4. Adjustment for body mass index (BMI) minimally affected the risks for diabetes and all‐cause/CVD mortality using CMDS.ConclusionCMDS can discriminate a wide range of risk for diabetes, CVD mortality, and all‐cause mortality independent of BMI, and should be studied as a risk assessment tool to guide interventions that prevent and treat cardiometabolic disease.