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To examine longitudinal changes in mood and empathy over the course of the internal medicine residency.The authors conducted a cohort study of 61 residents who completed the Profile of Mood States (POMS) and the Interpersonal Reactivity Index (IRI) at six time points during their internal medicine residency at a university-based program. (POMS was administered five times, and IRI was administered six times.) The main outcomes measured were trends in mood disturbances and multiple domains of empathy over the three-year residency, and comparisons to norms.Response rates varied from Time 1 to Time 6 (98%, 72%, 79%, 79%, 94%, and 95%, respectively). Interns had better scores on four POMS subscales: Depression–Dejection (p = .0031), Anger–Hostility (p < .0001), Fatigue–Inertia (p < .0001), and Vigor–Activity (p < .0001) compared with later administrations, especially midinternship. By the end of residency all POMS scores were returning towards baseline (effects sizes in the .20s), but only depression was no longer significantly different. IRI scores showed the decline in Empathic Concern remained over residency whereas Personal Distress peaked midinternship year but approached baseline at the end of residency. Compared with the general population, the graduating residents were less tense, depressed, and confused. Personal Distress was significantly lower than the norm group.Internal medicine residency presents challenges resulting in common mood disturbances. Although graduating residents appear to be better off than the population norms, some domains of their mood disturbances and empathy never fully recover from their internship year.