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Depression is common among training physicians and may disproportionately affect women. The identification of modifiable risk factors is key to reducing this disease burden and its negative impact on patient care and physician career attrition.To determine the presence and magnitude of a sex difference in depressive symptoms and work-family conflict among training physicians; and if work-family conflict impacts the sex difference in depressive symptoms among training physicians.A prospective longitudinal cohort study of medical internship in the United States during the 2015 to 2016 academic year in which 3121 interns were recruited across all specialties from 44 medical institutions.Prior to and during their internship year, participants reported the degree to which work responsibilities interfered with family life using the Work Family Conflict Scale and depressive symptoms using the Patient Health Questionnaire-9 (PHQ-9).Mean (SD) participant age was 27.5 (2.7) years, and 1571 participants (49.7%) were women. Both men and women experienced a marked increase in depressive symptoms during their internship year, with the increase being statistically significantly greater for women (men: mean increase in PHQ-9, 2.50; 95% CI, 2.26-2.73 vs women: mean increase, 3.20; 95% CI, 2.97-3.43). When work-family conflict was accounted for, the sex disparity in the increase in depressive symptoms decreased by 36%.Our study demonstrates that depressive symptoms increase substantially during the internship year for men and women, but that this increase is greater for women. The study also identifies work-family conflict as an important potentially modifiable factor that is associated with elevated depressive symptoms in training physicians. Systemic modifications to alleviate conflict between work and family life may improve physician mental health and reduce the disproportionate depression disease burden for female physicians. Given that depression among physicians is associated with poor patient care and career attrition, efforts to alleviate depression among physicians has the potential to reduce the negative consequences associated with this disease.