Objectives. Mindfulness-based stress reduction (MBSR) enhances short-term psychological health in clinical and non-clinical samples, whereas studies examining long-term effects are scarce. This study examined whether the effects of a 7-week MBSR programme on mental health persisted at 2-and 4-year follow up and explored possible mechanisms of effect. Methods. In a two-site randomized controlled trial, 288 medical and psychology students were allocated to an MBSR intervention (n = 144) or a no-treatment control group (n = 144). During the 4-year follow-up period, the MBSR group was offered 90-min booster sessions semi-annually. The primary outcome measures were mental distress (General Health Questionnaire-GHQ) and well-being; these were measured at baseline (T0) and postintervention follow-up at 1 month (T1), 2 years (T1) and again at 4 years (T3). Secondary outcomes included coping, mindfulness, and meditation practice. Results. At 4-year follow up, the MBSR group showed significantly better scores on mental distress, mindfulness, avoidance coping, and problem-focused coping (Cohen's d = 0.23-0.42). Meditation practice positively predicted long-term mindfulness scores. Short-term effects in mindfulness-scores mediated long-term intervention effects in mental distress and coping. However, reversed mediation also was observed (i.e. changes in outcome mediating long-term mindfulness scores), and this indicates that initial changes in outcome and mindfulness are intrinsically intertwined and may both influence long-term effects. Small post-intervention effects on well-being and seeking social support did not persist at follow up. Conclusions. MBSR fostered enduring effects on mental distress and coping in medical and psychology students 4 years post-intervention.