Sexual dimorphisms within the human brain are well-documented. Human immunodeficiency virus (HIV) infection is associated with atrophy and microstructural white matter alterations, yet sex-specific dimorphic brain alterations in persons living with HIV have not been systematically examined. To address this issue, we evaluated regional differences in normal-appearing white matter (NAWM) in adults with and without HIV utilizing diffusion tensor imaging. Through a voxel-by-voxel analytic approach, sexual dimorphisms in NAWM anisotropy and diffusivity were identified. In comparison to seronegative men and women, HIV infection contributed to a decline in the distribution of anisotropic differences between the sexes. Alterations in diffusivity were more complex, with seropositive women demonstrating an increase in regional diffusivity, while seropositive men demonstrated a reduction in regional differences. Sex by serostatus interactions within the left frontal lobe and bilateral thalamic region were identified. These results suggest that HIV contributes to sex-specific microstructural NAWM alterations, such that sex and serostatus differentially alter the integrity of the neuronal matrix.