BACKGROUND: Physicians need to learn and work amidst a plethora of uncertainties, which may drive burnout. Understanding differences in tolerance of uncertainty is an important research area. OBJECTIVE: To examine factors associated with tolerance of uncertainty, including well-being metrics such as burnout. DESIGN: Online confidential survey. SETTING: The Massachusetts General Physicians Organization (MGPO). PARTICIPANTS: All 2172 clinically active faculty in the MGPO. MAIN MEASURES: We examined associations for tolerance of uncertainty with demographic information, personal and professional characteristics, and physician well-being metrics. KEY RESULTS: Two thousand twenty (93%) physicians responded. Multivariable analyses identified significant associations of lower tolerance of uncertainty with female gender (OR, 1.23; 95% CI, 1.03-1.48); primary care practice (OR, 1.56; 95% CI, 1.22-2.00); years since training (OR, 0.99; 95% CI, 0.98-0.995); and lacking a trusted advisor (OR, 1.25; 95% CI, 1.03-1.53). Adjusting for demographic and professional characteristics, physicians with low tolerance of uncertainty had higher likelihood of being burned-out (OR, 3.06; 95% CI, 2.41-3.88), were less likely to be satisfied with career (OR, 0.37; 95% CI, 0.26-0.52), and less likely to be engaged at work (RR, 0.87; 95% CI, 0.84-0.90). CONCLUSION: At a time when concern about physician well-being is high, with much speculation about causes of burnout, we found a strong relationship between tolerance of uncertainty and physician well-being, across specialties. Particular attention likely needs to be paid to those with less experience, those in specialties with high rates of undifferentiated illness and uncertainty, such as primary care, and ensuring all physicians have access to a trusted advisor. These results generate the potential hypothesis that efforts focused in understanding and embracing uncertainty could be potentially effective for reducing burnout. This concept should be tested in prospective trials.