Background. Long-term comorbidities such as cognitive impairment remain prevalent in otherwise effectively treated people living with human immunodeficiency virus (HIV). We investigate the relationship between cognitive impairment and brain structure in successfully treated patients using multimodal neuroimaging from the Comorbidity in Relation to AIDS (COBRA) cohort. Methods. Cognitive function, brain tissue volumes, and white matter microstructure were assessed in 134 HIV-infected patients and 79 controls. All patients had suppressed plasma HIV RNA at cohort entry. In addition to comprehensive voxelwise analyses of volumetric and diffusion tensor imaging, we used an unsupervised machine learning approach to combine cognitive, diffusion, and volumetric data, taking advantage of the complementary information they provide. Results. Compared to the highly comparable control group, cognitive function was impaired in 4 of the 6 cognitive domains tested (median global T-scores: 50.8 vs 54.2; P <.001). Patients had lower gray but not white matter volumes, observed principally in regions where structure generally did not correlate with cognitive function. Widespread abnormalities in white matter microstructure were also seen, including reduced fractional anisotropy with increased mean and radial diffusivity. In contrast to the gray matter, these diffusion abnormalities correlated with cognitive function. Multivariate neuroimaging analysis identified a neuroimaging phenotype associated with poorer cognitive function, HIV infection, and systemic immune activation. Conclusions. Cognitive impairment, lower gray matter volume, and white matter microstructural abnormalities were evident in HIV-infected individuals despite fully suppressive antiretroviral therapy. White matter abnormalities appear to be a particularly important determinant of cognitive dysfunction seen in well-treated HIV-infected individuals.