Despite decades of research, there is still no agreement over the presence of gender-based morphologic differences in the human corpus callosum. We approached the problem using a highly precise computational technique for shape comparison. Starting with a prospectively acquired sample of cranial MRIs of healthy volunteers (age ranges 18-84), the variations of individual callosa are quantified with respect to a reference callosum shape in the form of Jacobian determinant maps derived from the geometric transformations that map the reference callosum into anatomic alignment with the subject callosa. Voxelwise t tests performed over the determinant values demonstrated that females had a larger splenium than males (P < 0.001 uncorrected for multiple comparisons) while males possessed a larger genu (P < 0.001). In addition, pointwise Pearson plots using age as a correlate showed a different pattern of age-related changes in male and female callosa, with female splenia tending to expand more with age, while the male genu tended to contract. Our results demonstrate significant morphologic differences in the corpus callosum between genders and a possible sex difference in the neuro-developmental cycle.