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Background Physician burnout affects many physicians and is associated with decreased patient safety and physician health. Mindfulness curricula can reduce burnout but are often impractical to implement during residency. Objectives: To determine how a novel 6-month mindfulness curriculum designed for pediatric trainees impacts physician burnout, mindfulness, and empathy. Methods 15 pediatric residency programs’ interns participated in a stratified, cluster randomized controlled trial of the “Mindfulness Intervention for New Interns” (MINdI) curriculum. Participants completed the Maslach Burnout Inventory, Five Facet Mindfulness Questionnaire, and 2 Interpersonal Reactivity Index empathy scales and measures of mindfulness-related knowledge, attitudes and behaviors. Burnout was defined as an emotional exhaustion (EE) score >= 27 or a depersonalization (DP) score >= 10. The primary outcome was EE score. Missing data was addressed by conducting 20 data imputations. To determine impact of study arm on outcomes, we conducted logistic and GEE regressions clustered on site while controlling for factors that differed by arm. Results 340/365 invited interns completed the baseline survey (93.1%), and 254 completed follow-up (69.6%). At baseline, the mean EE score of the MINdI and control arms did not significantly differ (coef. -0.25; 95% CI: -4.54, 4.04), but the odds of burnout was significantly higher in the MINdI arm than controls (OR 2.73; 95% CI: 1.005, 7.43). Compared to controls, there were significantly higher mindfulness-related knowledge, attitudes, and behavior and higher EE scores in the MINdI arm at follow-up (coef. 2.45; 95% CI: 0.90, 6.66). At follow-up, burnout, mindfulness, or empathy scores did not significantly differ by arm. Conclusion Interns randomized to experience MINdI had higher EE despite increased knowledge, attitudes, and behaviors about mindfulness. The MINdI curriculum did not affect burnout, mindfulness nor empathy. As the curricula improved some measures of learning but increased EE future rigorous study of curricula to reduce physician burnout is needed.