Neuropathology has defined novel HIV-specific diseases at tissue level: HIV encephalitis and HIV leukoencephalopathy. Both occur usually in the later stages of the AIDS infection and consistently demonstrate large amounts of HIV products. In contrast to this HIV-specific neuropathology, HIV-associated neuropathology features unspecific syndromes with disputed relation to HIV infection: myelin pallor, vacuolar myelopathy, vacuolar leukoencephalopathy, lymphocytic meningitis, and diffuse poliodystrophy. All types of neuropathology may contribute to clinical manifestation according to severity, extent, and distribution of lesions, but clinico-pathologic correlation may be poor in the individual case. Neuropathologic and other data suggest two major pathogenetic pathways of HIV-associated CNS damage: First, systemic and local increase of the virus load leads to HIV encephalitis or HIV leukoencephalopathy; this is corroborated by prominent HIV production within such lesions. Second, neuronotoxicity by HIV proteins or factors secreted from infected cells is supported by histological changes of diffuse poliodystrophy and by morphometric loss of frontocortical neurons.