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Background There are contradicting reports on the associations between Apolipoprotein E4 (ApoE e4) and brain outcomes in HIV with some evidence that relationships may be greatest in older age groups. Methods We assessed cognition in 76 clinically stable HIV-infected participants over age 60 and genotyped ApoE. Sixty-one of these subjects underwent structural brain magnetic resonance imaging and diffusion tensor imaging. Results The median age of the participants was 64 years (range: 60-84) and the median estimated duration of HIV infection was 22 years. Apo e4 carriers (n = 19) were similar to noncarriers (n = 57) in sex (95% vs. 96% male), and education (16.0 vs. 16.2 years) ApoE e4 carriers demonstrated greater deficits in cognitive performance in the executive domain (P = 0.045) and had reduced fractional anisotropy and increased mean diffusivity throughout large white matter tracts within the brain compared with noncarriers. Tensor-based morphometry analyses revealed ventricular expansion and atrophy in the posterior corpus callosum, thalamus, and brainstem among HIV-infected ApoE e4 carriers compared with e4 noncarriers. Conclusions In this sample of older HIV-infected individuals, having at least 1 ApoE e4 allele was associated with decreased cognitive performance in the executive functioning domain, reduced brain white matter integrity, and brain atrophy. Brain atrophy was most prominent in the posterior corpus callosum, thalamus, and brainstem. This pattern of cognitive deficit, atrophy, and damage to white matter integrity was similar to that described in HIV, suggesting an exacerbation of HIV-related pathology; although emergence of other age-associated neurodegenerative disorders cannot be excluded.