Being able to predict medical school performance is essential to help ensure the supply of quality physicians. The purpose of our study was to examine the influence of gender and age on academic performance (AP) and on academic difficulty (AD). The study involved all matriculants of 3 classes at one medical school. Independent variables included gender, age (categorized into younger and older than 23 years) and the gender by age interaction. Dependent variables included an AP scale score, a clinically based performance examination and AD. The Wilson AP Scale score was developed to assess both excellent and poor performance. The Wilson AP Scale included first-, second-, and third-year medical school grade-point-averages, USMLE Step 1score and USMLE Step 2 score. Older women as a group had the highest mean Wilson AP Scale score. Women performed better than men on the clinically based performance examinations. Younger men were least likely to have AD and younger women were most likely to have AD. Five of 123 younger men versus 13/66 older men had AD. Also, 15/63 younger women had AD versus 2/27 older women. A significant gender by age interaction was present in predicting the Wilson AP Scale score (p = 0.009) and AD (p = 0.002). Older women performed better than both older men and younger women in 3 classes of medical students at one medical school. A significant gender by age interaction was predictive of AP and AD. These findings may have implications on admission decisions.