Recent evidence suggests that examination of host genetics may contribute to identification of HIV-seropositive individuals at risk for developing neurocognitive impairment. Specifically, HIV-seropositive carriers of a known risk factor for developing Alzheimer's disease, i.e., the apolipoprotein E (APOE) _4 allele, reportedly demonstrate a nearly threefold increased risk for HIV-associated dementia (HAD) in some studies. In the present study, the relationship of APOE _4 carrier status to the spectrum of HIV-associated neurocognitive impairment was examined in a sample of 276 well-characterized HIV-seropositive individuals, stratified by ethnicity. It was hypothesized that APOE _4 carrier status would be associated with increased risk for all levels of impairment, particularly greater severity of impairment, and the pattern of APOE _4-related domain impairment was explored. Overall, the results of the current study suggest that carrying an APOE _4 proxy allele confers greater risk for moderate-severe HIV-associated neurocognitive impairment in Caucasians based on associations observed using a proxy single nucleotide polymorphism (SNP) in high linkage disequilibrium with APOE. The study failed to demonstrate a hypothesized relationship between APOE _4 proxy carrier status and milder forms of neurocognitive impairment in HIV, and no APOE _4 proxy carrier effect was observed for any analyses in the African American group. Results also suggest that Caucasian carriers of the APOE _4 proxy allele were more likely to demonstrate memory and motor impairment, which are the domains that have been shown to be the most sensitive to HIV infection. As such, these domain-level findings provide additional, albeit tentative, support for the potential role of APOE _4 in increasing risk for HIV-associated neurocognitive impairment. Implications of these findings are discussed, and limitations to the study are also presented, with particular emphasis on limitations to conclusions regarding associations between APOE genotype and HIV-associated neurocognitive impairment based on the use of a proxy SNP.