Background: Although medical student specialty choices shape the future of the healthcare workforce, factors influencing changes in specialty preference during training remain poorly understood. Aim: To explore if medical student distress and empathy predicts changes in students' specialty preference. Methods: A total of 858/1321 medical students attending five medical schools responded to surveys in 2006 and 2007. The survey included questions about specialty choice, burnout, depression, quality of life, and empathy. Results: A total of 26% (205/799) changed their specialty preference over 1 year. Depersonalization an aspect of burnout was the only distress variable associated with change in specialty preference (OR, odds ratio 0.962 for each 1-point increase in score, p=0.03). Empathy at baseline and changes in empathy over the course of 1 year did not predict change in specialty preference (all p>0.05). On multi-variable analysis, being a third year (OR 1.92), being male (OR 1.48), and depersonalization score (OR 0.962 for each point increase) independently predicted a change in specialty preference. Distress and empathy did not independently predict students' losing interest in primary care whereas being a fourth-year student (OR 1.83) and being female (OR 1.83) did. Conclusion: Among those who did have a major change in their specialty preference, distress and empathy did not play a major role.