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Purpose: Personality traits are associated with psychophysiological stress, but few studies focus on medical students. This study aimed to better understand the association of personality traits with the efficacy of stress management interventions for medical students., Method: A randomized controlled trial was conducted with fourth-year students who took the objective structured clinical examination at Bernard University Lyon 1 in December 2021. Students were randomized in cardiac biofeedback, mindfulness, and control groups. Each intervention was implemented for 6 minutes before the examination. Physiological stress levels were collected during the intervention. Psychological stress levels were rated by students at baseline and after the intervention. Personality traits were assessed via the Big-Five Inventory. Interactions between personality traits and the efficacy of the interventions were analyzed using multivariable linear regression models., Results: Four hundred eighty-one students participated. Higher baseline psychological stress levels were associated with higher neuroticism and agreeableness ( β = 10.27 [95% confidence interval {CI}, 7.40-13.13; P < .001] and β = 3.42 [95% CI, 0.98-5.85; P = .006], respectively) and lower openness ( β = -4.95; 95% CI, -7.40 to -2.49; P < .001). As compared with the control intervention, both stress management interventions led to lower levels of psychological ( P < .001 for both) and physiological stress levels (biofeedback: P < .001 and mindfulness: P = .009). Biofeedback efficacy varied by extraversion score for psychological ( β = -5.66; 95% CI, -10.83 to -0.50; P = .03) and physiological stress reduction ( β = -0.002; 95% CI, -0.003 to -0.00004; P = .045). Mindfulness efficacy varied by agreeableness score for psychological stress reduction ( β = -7.87; 95% CI, -13.05 to -2.68; P = .003)., Conclusions: Students with a high score in extraversion may benefit more from biofeedback interventions, while students with high scores in agreeableness may benefit more from mindfulness interventions., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Association of American Medical Colleges.)