HIV-associated dementia (HAD) is a serious neuropsychiatric disorder affecting people with AIDS. Host genotype may affect the pathogenesis of HIV in the central nervous system (CNS). One gene relevant to the individual variation in acquiring HAD may be Apolipoprotein E (ApoE). We aimed to investigate the relationship of ApoE genotype to neuropsychological function and white matter integrity of the corpus callosum in a region of interest a priori analysis of HIV-positive subjects with clade C HIV. Forty-five subjects underwent ApoE genotyping, neuropsychological testing, and diffusion tensor imaging (DTI). Subjects (n = 24) with at least one ε4 allele when compared to subjects with no ε4 allele (n = 19) had significantly decreased immediate and delayed recall on the Hopkins Verbal Learning test (p = 0.05) and significantly decreased fractional anisotrophy in the corpus callosum (p = 0.007). These data indicate that the ε4 allelic variant of ApoE is associated with memory impairment and white matter damage of the corpus callosum in HIV-positive subjects.