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Medical practice is inherently ambiguous and uncertain. The physicians’ ability to tolerate ambiguity and uncertainty has been proved to have a great impact on clinical practice. The primary aim of the present study was to test the hypothesis that higher degree of physicians’ ambiguity and uncertainty intolerance and higher need for cognitive closure will predict higher work stress. Two hundred and twelve physicians (mean age = 42.94 years; SD = 10.72) from different medical specialties with different levels of expertise were administered a set of questionnaires measuring perceived levels of work-related stress, individual ability to tolerate ambiguity, stress deriving from uncertainty, and personal need for cognitive closure. A linear regression analysis was performed to examine which variables predict the perceived level of stress. The regression model was statistically significant [R2 = .32; F(10,206) = 8.78, p ≤ .001], thus showing that, after controlling for gender and medical specialty, ambiguity and uncertainty tolerance, decisiveness (a dimension included in need for closure), and the years of practice were significant predictors of perceived work-related stress. Findings from the present study have some implications for medical education. Given the great impact that the individual ability to tolerate ambiguity and uncertainty has on the physicians’ level of perceived work-related stress, it would be worth paying particular attention to such a skill in medical education settings. It would be crucial to introduce or to empower educational tools and strategies that could increase medical students’ ability to tolerate ambiguity and uncertainty. Abbreviations:JSQ: Job stress questionnaire; NFCS: Need for cognitive closure scale; PRU: Physicians’ reactions to uncertainty; TFA: Tolerance for ambiguity [ABSTRACT FROM PUBLISHER]