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Human immunodeficiency virus type 1 (HIV‐1) infection of the central nervous system is associated with characteristic virological, clinical, and neuropathological findings in adults and children. Productive infection in the brain and spinal cord occurs in blood‐derived macrophages, resident microglia, and multinucleated giant cells. Previous work implicated indirect mechanisms for neurotoxicity by HIV‐1 gene products or by factors secreted from HIV‐1‐infected macrophages. However, this cannot explain the paradox between the small numbers of infected cells and the widespread tissue pathology. Based on recent studies from our laboratories, we suggest that HIV‐1‐infected macrophages can initiate neurotoxicity, which is then amplified through cell‐to‐cell interactions with astrocytes. Macrophageastrocyte interactions produce cytokines tumor necrosis factor‐α and interleukin‐1b̃ and arachidonic metabolites that …