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Background: Functional impairment, malnutrition and fluid overload are prevalent in patients undergoing maintenance hemodialysis (MHD). The extracellular water/body cell mass ratio (ECW/BCM) is a new indicator reflecting fluid overload and malnutrition. A previous study has suggested that it performs better than other indices in assessing fluid status. This study investigates the relationship between pre-dialysis whole-body ECW/BCM and physical function in MHD patients. Methods: We conducted a multicenter, cross-sectional study in Guizhou Province in Southwest China. The Karnofsky Performance Status (KPS) was used to evaluate patients' functional status. Patients with KPS scores of = 80 were considered to have a functional impairment. The body composition was measured using the body composition monitor (BCM), and the value of the ECW/BCM ratio was calculated. The subjects were classified into three groups according to ECW/BCM tertiles. Multiple logistic regression models and interactive analyses were conducted. Results: The final analysis included 2818 subjects. Multivariate logistic regression analyses showed that compared with the lowest tertile (tertile 1), the adjusted odds ratio of functional impairment were 1.95 (95% CI: 1.21-3.13, p < 0.001) and 2.10 (95% CI: 1.31-3.37, p < 0.001) in the second and the third tertiles of ECW/BCM, respectively after adjusting for age, sex, current smoking status, history of stroke, heart failure, diabetes, and myocardial infarction. Subgroup analysis showed that the association existed stably across all subgroups stratified by age, gender, cognitive impairment (CI), history of stroke, heart failure, and diabetes (all p values for interaction >0.05). Conclusions: Elevated ECW/BCM is independently linked to an increased risk of functional impairment in patients with MHD. [ABSTRACT FROM AUTHOR]