['To determine the association of markers of regional neurodegeneration (ND) at autopsy to degree of neurocognitive impairment in persons with HIV.', 'In a prospectively followed cohort of HIV-infected individuals we examined the relationship between antemortem neuropsychological (NP) abilities and postmortem neuropathological data.', 'Twenty-seven HIV-infected individuals with both neuropsychological and neuropathological data were identified. Laser confocal scanning microscopy was used to determine the degree of ND based on: (1) microtubule-associated protein (MAP2; reflecting neuronal cell bodies and dendrites) and (2) synaptophysin (SYN; a measure of presynaptic terminals). A regional combined score, based on the distribution of percentage neuropil occupied by MAP2 and SYN and emphasizing severity of ND, was created for each brain region: midfrontal cortex, hippocampus, and putamen.', 'The regional combined scores from each brain region studied were better correlated with level of global NP impairment than measures of SYN and MAP2 individually. In a regression, hippocampal and putamen regional combined scores were independent predictors of degree of antemortem NP impairment (F(3,23) = 6.17; P < 0.01; R2 = 0.45). The correlations among regional ND measures demonstrated that ND is unevenly distributed across multiple brain regions.'] Is cortical and subcortical neurodegeneration associated with HIV neurocognitive impairment?