Although muscle mass and its distribution have been shown to affect prognosis, the association between regional muscle mass and cardiovascular mortality risk in diabetic patients remains unclear.This prospective cohort study analyzed data from 2166 individuals with diabetes who participated in the National Health and Nutrition Survey conducted in the United States between 2003 to 2006 and 2011 to 2018, linked to the National Death Index. Weighted Kaplan-Meier analysis and multivariable Cox proportional hazards models were used to explore the association between different regional lean mass and cardiovascular mortality.The weighted Kaplan-Meier analysis revealed statistically significant differences in survival probabilities across lean upper limbs, lean lower limbs, lean gynoid, and lean trunk mass levels in diabetic participants (P < 0.05). In the multivariate adjusted Cox proportional hazards models, higher levels of upper limb lean mass were found to be associated with decreased cardiovascular mortality (hazard ratio, 0.589; 95% confidence interval, 0.332-0.976; P = 0.041). Notably, this correlation was more significant in men (hazard ratio, 0.378; 95% confidence interval, 0.171-0.834; P = 0.016), which was indicated by the results of the Cox regression and nonlinear regression analysis.Higher upper limb lean mass is associated with lower cardiovascular mortality compared with other regional lean mass in patients with diabetes, especially for men. Further research is needed to elucidate the mechanisms involved in muscle metabolic differentiation.Copyright © 2024 Elsevier Inc. All rights reserved.