The relationship between cognitive impairment and white-matter integrity in human immunodeficiency virus (HIV) remains poorly understood, particularly in clade C. The authors utilized diffusion tensor imaging (DTI) and a comprehensive neuropsychological evaluation to investigate the relationship between cognitive impairment and white-matter integrity in HIV-positive subjects with clade C HIV. Forty-four HIV-infected individuals and 10 seronegative subjects were compared, using a whole-brain, voxel-based approach to define fractional anisotropy (FA) and mean diffusion (MD). Compared with healthy-control subjects, the HIV-infected group exhibited decreased FA in the corpus callosum, superior longitudinal fasciculus, and cingulum and sagittal stratum. This study provides evidence that white-matter integrity is compromised in individuals infected with clade C HIV.