CONTEXT Although the prevalence of depression among medical interns substantially exceeds that of the general population, the specific factors responsible are not well understood. Recent reports of a moderating effect of a genetic polymorphism (5-HTTLPR) in the serotonin transporter protein gene on the likelihood that life stress will precipitate depression may help to understand the development of mood symptoms in medical interns. OBJECTIVES To identify psychological, demographic, and residency program factors that are associated with depression among interns and to use medical internship as a model to study the moderating effects of this polymorphism. DESIGN A prospective cohort study. SETTING Thirteen US hospitals. PARTICIPANTS Seven hundred forty interns entering participating residency programs. MAIN OUTCOME MEASURES Subjects were assessed for depressive symptoms using the 9-item Patient Health Questionnaire (PHQ-9), a series of psychological traits, and the 5-HTTLPR genotype prior to internship and then assessed for depressive symptoms and potential stressors at 3-month intervals during internship. RESULTS The PHQ-9 depression score increased from 2.4 prior to internship to a mean of 6.4 during internship (P < .001). The proportion of participants who met PHQ-9 criteria for depression increased from 3.9% prior to internship to a mean of 25.7% during internship (P < .001). A series of factors measured prior to internship (female sex, US medical education, difficult early family environment, history of major depression, lower baseline depressive symptom score, and higher neuroticism) and during internship (increased work hours, perceived medical errors, and stressful life events) was associated with a greater increase in depressive symptoms during internship. In addition, subjects with at least 1 copy of a less-transcribed 5-HTTLPR allele reported a greater increase in depressive symptoms under the stress of internship (P = .002). CONCLUSIONS There is a marked increase in depressive symptoms during medical internship. Specific individual, internship, and genetic factors are associated with the increase in depressive symptoms.Published online April 5, 2010 (doi:10.1001/archgenpsychiatry.2010.41).Arch Gen Psychiatry. 2010;67(6):557-565-->