Background Multiple factors influence the decision to enter a career in medicine and choose a specialty. Previous studies have looked at personality differences in medicine but often were unable to describe the heterogeneity that exists within each specialty. Our study used a person-centered approach to characterize the complex relations between the personality profiles of resident physicians and their choice of specialty. Methods 169 resident physicians at a large Midwestern US training hospital completed the Temperament and Character Inventory (TCI) and the Satisfaction with Life Scale (SWLS). Clusters of personality profiles were identified without regard to medical specialty, and then the personality clusters were tested for association with their choice of specialty by co-clustering analysis. Life satisfaction was tested for association with personality traits and medical specialty by linear regression and analysis of variance. Results We identified five clusters of people with distinct personality profiles, and found that these were associated with particular medical specialties Physicians with an “investigative” personality profile often chose pathology or internal medicine, those with a “commanding” personality often chose general surgery, “rescuers” often chose emergency medicine, the “dependable” often chose pediatrics, and the “compassionate” often chose psychiatry. Life satisfaction scores were not enhanced by personality-specialty congruence, but were related strongly to self-directedness regardless of specialty. Conclusions The personality profiles of physicians were strongly associated with their medical specialty choices. Nevertheless, the relationships were complex: physicians with each personality profile went into a variety of medical specialties, and physicians in each medical specialty had variable personality profiles. The plasticity and resilience of physicians were more important for their life satisfaction than was matching personality to the prototype of a particular specialty.