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A possible mechanism related to neurocognitive impairment (NCI) was investigated in 52 people with HIV receiving stable antiretroviral therapy and a matched comparison group of 31 HIV-uninfected controls. Cytomegalovirus immunoglobulin (CMV-IgG) levels were measured, and a neurocognitive test battery was administered to both groups. NCI was defined as a global deficit scale score equal or greater than .5. NCI was detected in 30.8% of persons with HIV and had an odds ratio of 5.15 over the comparison group. CMV-IgG levels were not significantly related to total NCI scores. However, a subgroup with high levels of CMV-IgG was associated with delayed neurocognitive processing speed. Additional studies of CMV-specific CD4+T-cell responses increased the probability of NCI with an odds ratio of 1.68. Also, other CD4 measures showed similar relationships. Larger studies, especially longitudinal ones, are necessary to validate these preliminary findings of a relationship between cytomegalovirus and cognitive functioning in people with HIV.