To investigate the possible influence of virus tropism on SIV-induced neuropathogenesis, macaques were infected with molecularly cloned SIVmac239 which replicates poorly in cultured macrophages, with SIVmac251/32H which is a macrophage-tropic biologic clone, and with SIVmac251/MPBMC which is an early passage of 32H with enhanced replication competence in macrophages. We found that inflammatory as well as neuropathologic changes were identical in all clinically affected animals, irrespective of the in vitro tropism of the inocula. Moribund animals exhibited SIV encephalitis characterized by overt infection of macrophages/microglia inside the CNS parenchyma. Additionally, neuropathology of moribund animals was characterized by extraparenchymal immunopathology (meninges, perivascular space, choroid plexus stroma) and subtle white matter degeneration with glial changes, often associated with infected macrophages in situ (except in leukoencephalopathy). However, in animals inoculated with the lymphocyte-tropic and enhanced macrophage-tropic inocula, microglia but not blood-derived macrophages were the primary cells infected. Altogether, our results underline the significance of macrophage infection for the development of SIV encephalitis, and suggest that SIVmac239 either undergoes a change in cell tropism in vivo that results in the ability to replicate in macrophages, or else macrophages become more permissive to infection by this virus in the terminal stage of immunosuppressive disease.