To determine the neuropathological substrate of human immunodeficiency virus (HIV)‐associated neurocognitive disorders, we examined persons with acquired immunodeficiency syndrome before their death and related their antemortem neuropsychological performance to postmortem indicators of HIV encephalitis, viral burden, and presynaptic and postsynaptic neuronal injury. Of 20 prospectively examined cases, 9 were neurocognitively normal, 5 showed neuropsychological impairment, 5 had minor cognitive/motor disorder, and 1 was demented. Degree of neurocognitive impairment was strongly related to the amount of dendritic simplification based on microtubule‐associated protein 2 immunohistochemical staining, somewhat less so to a semiquantitative viral burden score based on numbers of HIV gp41‐immunoreactive cells, and much less so to the presence of multinucleated giant cells or microglial nodules. It appears that even milder neurocognitive impairment reflects microneuroanatomical injury to synaptic structures.