BackgroundStress-related disorders are a growing public health concern. While stress is a natural and adaptive process, chronic exposure to stressors can lead to dysregulation and take a cumulative toll on physical and mental well-being. One approach to coping with stress and building resilience is through Mindfulness-Based Stress Reduction (MBSR). By understanding the neural mechanisms of MBSR, we can gain insight into how it reduces stress and what drives individual differences in treatment outcomes. This study aims to establish the clinical effects of MBSR on stress regulation in a population that is susceptible to develop stress-related disorders (i.e., university students with mild to high self-reported stress), to assess the role of large-scale brain networks in stress regulation changes induced by MBSR, and to identify who may benefit most from MBSR.MethodsThis study is a longitudinal two-arm randomised, wait-list controlled trial to investigate the effects of MBSR on a preselected, Dutch university student population with elevated stress levels. Clinical symptoms are measured at baseline, post-treatment, and three months after training. Our primary clinical symptom is perceived stress, with additional measures of depressive and anxiety symptoms, alcohol use, stress resilience, positive mental health, and stress reactivity in daily life. We investigate the effects of MBSR on stress regulation in terms of behaviour, self-report measures, physiology, and brain activity. Repetitive negative thinking, cognitive reactivity, emotional allowance, mindfulness skills, and self-compassion will be tested as potential mediating factors for the clinical effects of MBSR. Childhood trauma, personality traits and baseline brain activity patterns will be tested as potential moderators of the clinical outcomes.DiscussionThis study aims to provide valuable insights into the effectiveness of MBSR in reducing stress-related symptoms in a susceptible student population and crucially, to investigate its effects on stress regulation, and to identify who may benefit most from the intervention.Trial registrationRegistered on September 15, 2022, at clinicaltrials.gov,NCT05541263.