Entering medical students experience distress symptoms due to the demands of the intensive curriculum, adjustment to new environments and increased responsibilities. The purpose of this controlled, randomized study was to determine the effects of a structured wellness program on measures of anxiety, depression and frequency of acute illness in 449 first year medical students. The effects of eight sessions of stress management were compared to a wait list control group. High risk students were identified based on scores on psychological inventories and number of recent life events (WLE). Results showed that depression, anxiety scores and frequency of acute illness were higher in women than in men, and were higher in students with multiple life events. Significant decreases were observed in depression in the intervention group students when WLE was the covariate (p = .045). Further, the high risk group showed consistently lower depression scores after the intervention compared to high risk wait list controls (p = .003), and these changes were maintained at the end of school year. There were no significant changes in anxiety or frequency of acute illness. Wellness programs can be implemented in medical school and may be particularly useful for entering students with elevated psychological distress.