Background and objectiveStress 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.