IMPORTANCE Despite the documented prevalence and clinical ramifications of physician distress, few rigorous studies have tested interventions to address the problem. OBJECTIVE To test the hypothesis that an intervention involving a facilitated physician small-group curriculum would result in improvement in well-being. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of 74 practicing physicians in the Department of Medicine at the Mayo Clinic in Rochester, Minnesota, conducted between September 2010 and June 2012. Additional data were collected on 350 nontrial participants responding to annual surveys timed to coincide with the trial surveys. INTERVENTIONS The intervention involved 19 biweekly facilitated physician discussion groups incorporating elements of mindfulness, reflection, shared experience, and small-group learning for 9 months. Protected time (1 hour of paid time every other week) for participants was provided by the institution. MAIN OUTCOMES AND MEASURES Meaning in work, empowerment and engagement in work, burnout, symptoms of depression, quality of life, and job satisfaction assessed using validated metrics. RESULTS Empowerment and engagement at work increased by 5.3 points in the intervention arm vs a 0.5-point decline in the control arm by 3 months after the study (P = .04), an improvement sustained at 12 months (+5.5 vs +1.3 points; P = .03). Rates of high depersonalization at 3 months had decreased by 15.5% in the intervention arm vs a 0.8% increase in the control arm (P = .004). This difference was also sustained at 12 months (9.6% vs 1.5% decrease; P = .02). No statistically significant differences in stress, symptoms of depression, overall quality of life, or job satisfaction were seen. In additional comparisons including the nontrial physician cohort, the proportion of participants strongly agreeing that their work was meaningful increased 6.3% in the study intervention arm but decreased 6.3% in the study control arm and 13.4% in the nonstudy cohort (P = .04). Rates of depersonalization, emotional exhaustion, and overall burnout decreased substantially in the trial intervention arm, decreased slightly in the trial control arm, and increased in the nontrial cohort (P = .03, .007, and .002 for each outcome, respectively). CONCLUSIONS AND RELEVANCE An intervention for physicians based on a facilitated small-group curriculum improved meaning and engagement in work and reduced depersonalization, with sustained results at 12 months after the study. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01159977.