The ability to mentally manipulate objects in three dimensions is essential to the practice of many clinical medical specialties. The relationship between this type of visual-spatial ability and performance in preclinical courses such as medical gross anatomy is poorly understood. This study determined if visual-spatial ability is associated with performance on practical examinations, and if students' visual-spatial ability improves during medical gross anatomy. Three hundred and fifty-two first-year medical students completed the Mental Rotations Test (MRT) before the gross anatomy course and 255 at its completion in 2008 and 2009. Hypotheses were tested using logistic regression analysis and Student's t-test. Compared with students in the lowest quartile of the MRT, students who scored in the highest quartile of the MRT were 2.2 [95% confidence interval (CI) 1.2 and 3.8] and 2.1 (95% CI 1.2 and 3.5) times more likely to score greater than 90% on practical examinations and on both practical and written examinations, respectively. MRT scores for males and females increased significantly (P less than 0.0001). Measurement of students' pre-existing visual-spatial ability is predictive of performance in medical gross anatomy, and early intervention may be useful for students with low visual-spatial ability on entry to medical school. Participation in medical gross anatomy increases students' visual-spatial ability, although the mechanism for this phenomenon is unknown.