Objectives:To examine the relationship between the humoral immune response and viral envelope diversity among HIV/AIDS patients with or without HIV-associated dementia (HAD).Methods:Whole blood and sera were collected from age- and disease-progression matched AIDS-defined patients with and without neuro-cognitive impairment at two centers. Peripheral blood mononuclear cells were isolated from whole blood and separated into monocyte/macrophage and peripheral blood lymphocyte (PBL) preparations. Genomic DNA, isolated from the PBL population, was used as template to amplify HIV-1 C2V3 envelope sequences in a nested PCR protocol. The resulting fragments were sequenced and subjected to a phylogenetic analysis.Results:Sera from non-demented (ND; n = 21) patients neutralized infection of CCR5-dependent, but not CXCR4-dependent viruses, more efficiently than sera from HAD patients (n = 15) (P< 0.05). A recombinant virus containing a brain derived C2V3 sequence was also neutralized less efficiently by sera from HAD patients (P< 0.05). C2V3 envelope sequences amplified from PBL revealed significantly greater diversity within the V3 region from HAD compared with ND patients (P< 0.001). The number of non-synonymous substitutions was positively correlated with the severity of neuro-cognitive impairment of patients (P< 0.005). Similarly, brain derived V3 sequences exhibited significantly increased diversity among HAD patients (P< 0.001).Conclusion:Our findings imply that HAD patients exhibited impaired serological responses that may lead to the emergence of viral mutants that potentially could infect the brain and mediate neurodegeneration.