Background: Medical students confront significant academic, psychosocial, and existential stressors throughout their training. Mindfulness-based stress reduction (MBSR) is an educational intervention designed to improve coping skills and reduce emotional distress. Purpose: The purpose of this study was to examine the effectiveness of the MBSR intervention in a prospective, nonrandomized, cohort-controlled study. Methods: Second-year students (n = 140) elected to participate in a 10-week MBSR seminar. Controls (n = 162) participated in a didactic seminar on complementary medicine. Profile of Mood States (POMS) was administered preintervention and postintervention. Results: Baseline total mood disturbance (TMD) was greater in the MBSR group compared with controls (38.7 ±33.3 vs. 28.0 ±31.2; p <. 01). Despite this initial difference, the MBSR group scored significantly lower in TMD at the completion of the intervention period (31.8 ±33.8 vs. 38.6 ±32.8; p < . 05). Significant effects were also observed on Tension-Anxiety, Confusion-Bewilderment, Fatigue-Inertia, and Vigor-Activity subscales. Conclusion: MBSR may be an effective stress management intervention for medical students.