Objective: 177 patients under maintenance hemodialysis were enrolled from four dialysis centers in 2016 and in 2020, and underwent bioelectrical impedance analysis just after hemodialysis. Patients were grouped into three groups by rank numbering in order of the percentage of skeletal muscle mass to dry body weight. The main outcome was intradialytic hypotension for the next three months after enrollment, defined as more than two episodes of hypotension (systolic blood pressure < 90 mmHg), requiring interventions. ROC curves to predict intradialytic hypotension were compared among multivariable logistic regression models including each parameters by bioelectrical impedance analysis. We compared three SMI groups using multivariable logistic regression models, and inverse probability of treatment weighting. Methods: Patients with a low skeletal muscle index (SMI) had a higher rate of intradialytic hypotension (41%). The low SMI group was female-dominant, more obese, more diabetic, and had lower handgrip strength than the other groups. In high SMI group, the risk of intradialytic hypotension was decreased (odds ratio [OR] = 0.08, [95% confidence interval (CI): 0.02–0.28]; adjusted OR = 0.06, [95% CI: 0.01–0.29]; OR, after inverse probability of treatment weighting = 0.71, [95% CI: 0.59-0.85]). When comparing AUC, models including skeletal muscle mass explained intradialytic hypotension better than model including clinical parameters only.  Results: This study suggested that the measurement and maintenance of skeletal muscle would be helpful in preventing intradialytic hypotension in frail hemodialysis patients.  Conclusions: Objective: Patients undergoing hemodialysis are susceptible to sarcopenia. This study was designed to determine the role of skeletal muscle mass in intradialytic hypotension. Methods: 177 patients under maintenance hemodialysis were enrolled from four dialysis centers in 2016 and in 2020, and underwent bioelectrical impedance analysis just after hemodialysis. Patients were grouped into three groups by rank numbering in order of the percentage of skeletal muscle mass to dry body weight. The main outcome was intradialytic hypotension for the next three months after enrollment, defined as more than two episodes of hypotension (systolic blood pressure < 90 mmHg), requiring interventions. ROC curves to predict intradialytic hypotension were compared among multivariable logistic regression models including each parameters by bioelectrical impedance analysis. We compared three SMI groups using multivariable logistic regression models, and inverse probability of treatment weighting. Results: Patients with a low skeletal muscle index (SMI) had a higher rate of intradialytic hypotension (41%). The low SMI group was female-dominant, more obese, more diabetic, and had lower handgrip strength than the other groups. In high SMI group, the risk of intradialytic hypotension was decreased (odds ratio [OR] = 0.08, [95% confidence interval (CI): 0.02–0.28]; adjusted OR = 0.06, [95% CI: 0.01–0.29]; OR, after inverse probability of treatment weighting = 0.71, [95% CI: 0.59-0.85]). When comparing AUC, models including skeletal muscle mass explained intradialytic hypotension better than model including clinical parameters only.  Conclusions: This study suggested that the measurement and maintenance of skeletal muscle would be helpful in preventing intradialytic hypotension in frail hemodialysis patients.