BACKGROUND AND OBJECTIVE: Stress and burnout impact resident physicians. This prospective study tests the hypothesis that a mindfulness-based resilience intervention would decrease stress and burnout in residents. METHODS: Resident physicians from the Departments of Family Medicine, Psychiatry, and Anesthesia at Duke University, Durham, NC, USA, participated in two or three 1-hour sessions of mindfulness-based resilience activities, which introduced mindful-awareness and included practical exercises for nurturing resilience. Anonymous surveys were distributed before (completed by 47 residents) and after the intervention (both completed by 30 residents); a follow-up survey was distributed 1 month later (seven residents completed all three surveys). The survey included the Depression Anxiety Stress Scale, 21-question version (DASS-21), the Oldenburg Burnout Inventory, the Mindful Attention Awareness Scale, and ten questions from the Cognitive Failures Questionnaire. RESULTS: At baseline, most residents' scores were in the normal range with respect to stress; however, female residents had higher DASS-21 scores than male residents (31.7, females vs 18.4, males; P=0.002). Most residents' burnout scores were in the abnormal range, both with respect to exhaustion (38/47 residents, subscore ≥2.25) and disengagement (37/47 residents, subscore ≥2.1). Higher perceived levels of stress correlated with the instruments. Analysis of the surveys before and after the intervention showed no significant short-term change in stress, burnout, mindful-awareness, or cognitive failure. There was a trend for females and post-medical school graduate year 1 and 2 (PGY1 and PGY2) residents to have a reduction in DASS-21 scores after intervention. There was also a trend of reduced stress and burnout in residents who perceived higher stress. CONCLUSION: Residents who are female, PGY1 and PGY2, and who perceive residency to be stressful may benefit most from a mindfulness-based resilience intervention.