In this brief review, we present a summary of the clinical presentation of HIV-associated dementia (HAD), HAD in the highly active antiretroviral therapy (HAART) era, the immunopathogenesis of HAD, and the possible role of a recently described novel macrophage-derived protein in HAD. Different aspects of the clinical presentation of HAD will be reviewed as well as the results of recent autopsy studies demonstrating that although HAART dramatically decreased the incidence of opportunistic infections and malignancies in the central nervous system, it has reduced but not eliminated HIV encephalopathy. This suggests a direct cytopathic effect of HIV on neuronal tissue. Consequently, the immunopathogenesis of HAD and the role of neurotoxins produced by brain macrophages and microglial cells will be reviewed including the possible role of a recently cloned macrophage-derived proapoptotic factor, soluble HIV apoptotic protein (SHIVA) identified in our laboratory. HAART therapy reduces the incidence of opportunistic infections, the direct pathogenic effect of HIV, especially on neuronal tissue, may become of increasing importance.