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Purpose: After weaning from cardiopulmonary bypass (CPB), the radial artery pressure is frequently lower than the central pressure as reflected by femoral pressure. This discrepancy may cause improper blood pressure management. In this study, we aimed to evaluate the risk factors related to developing a significant postbypass femoral-to-radial pressure gradient, including the incidence of complications related to femoral pressure monitoring. Methods: From January 2017 to May 2021, we studied consecutive adult cardiovascular surgical patients undergoing CPB in a historical cohort study. Patients were divided into two groups according to developing a significant femoral-to-radial pressure gradient, which was defined as a difference of ≥ 25 mm Hg for systolic pressure or ≥ 10 mm Hg for mean pressure, lasting ≥ 5 minutes for 30 minutes after CPB weaning. Factors associated with a significant pressure gradient and femoral pressure monitoring-related complications were analyzed. Results: Among 2,019 patients, 677 (34%) showed a significant postbypass femoral-to-radial pressure gradient. Multivariable logistic regression analysis revealed the following factors related to the pressure gradient development: age (adjusted odds ratio [aOR] for an increase in 10 years, 1.09; 95% confidence interval [CI], 1.04 to 1.09; P< 0.001), body surface area (BSA) (aOR for an increase in 1 m2, 0.12; 95% CI, 0.07 to 0.21; P< 0.001), aortic cross-clamping time (aOR for an increase in 30 minutes, 1.05; 95% CI, 1.03 to 1.08; P< 0.001), and intraoperative epinephrine use (aOR, 1.55; 95% CI, 1.23 to 1.95; P< 0.001). The femoral pressure monitoring-related complications were observed in 11/2,019 (0.5%) patients. Conclusion: Our study showed that old age, smaller BSA, prolonged aortic cross-clamping time, and intraoperative epinephrine use were associated with developing a significant postbypass femoral-to-radial pressure gradient in cardiovascular surgery. Considering monitoring-related complications occurred very infrequently, it might be helpful to monitor both radial and femoral pressure simultaneously in patients with these risk factors for appropriate blood pressure management. Nevertheless, further studies are needed to confirm our findings because our results are limited by a retrospective design and residual confounding factors.