ObjectiveTo determine the association between having simultaneously high body mass index (BMI) and high relative lean body mass (LBM) and cardio‐metabolic risk factors, metabolic syndrome (MetS), and diabetes in adults.Materials and MethodsA cross‐sectional analysis was performed on 4982 adults aged 19‐85 years that participated in the National Health and Nutrition Examination Survey (cycles 1999‐2000‐2005‐2006). The primary exposure variable was categorization into four groups: (a) Low‐BMI/Low‐LBM, (b) Low‐BMI/High‐LBM, (c) High‐BMI/Low‐LBM, and (d) High‐BMI/High‐LBM. LBM was assessed using dual‐energy X‐ray absorptiometry. The primary outcome measures were cardio‐metabolic risk factors, MetS based on the ATP III definition; participants were required to have at least three of the following five criteria: high waist circumference, low HDL cholesterol, elevated triglyceride levels, high resting blood pressure, and self‐reported diabetes.ResultsCompared to the High‐BMI/High‐LBM, most cardio‐metabolic risk factors were significantly different among groups (P < .05) while no such differences were observed for the High‐BMI/Low‐LBM (P > .05). Exception of waist circumference (OR [95%]: 21.8 [8.84‐53.82]), there was no increased odds of having cardio‐metabolic risk factors in the High‐BMI/Low‐LBM compared with the High‐BMI/High‐LBM (P > .05). The odds of having MetS and diabetes for the High‐BMI/Low‐LBM compared with the High‐BMI/High‐LBM were OR (95% CI): 1.68 (0.84‐3.36) and 0.59 (0.26‐1.34), respectively.ConclusionsOur results suggest that having a high‐BMI as well as high relative LBM levels is not associated with cardio‐metabolic risk factors, MetS, and diabetes. Therefore, maintaining a BMI below 30 kg/m2 appears to be clinically relevant, regardless of LBM levels.