Macrophage recruitment to the central nervous system (CNS) during AIDS pathogenesis is poorly understood. We measured the accumulation of brain perivascular (CD163⁺) and inflammatory (MAC387⁺) macrophages in SIV-infected monkeys. Monocyte progenitors were 5-bromo-2′-deoxyuridine (BrdU) labeled in bone marrow, and CNS macrophages were labeled serially with fluorescent dextrans injected into the cisterna magna. MAC387⁺ macrophages accumulated in the meninges and choroid plexus in early inflammation and in the perivascular space and SIV encephalitis (SIVE) lesions late. CD163⁺ macrophages accumulated in the perivascular space and SIVE lesions with late inflammation. Most of the BrdU⁺ cells were MAC387⁺; however, CD163⁺BrdU⁺ macrophages were present in the meninges and choroid plexus with AIDS. Most (81.6%á▒á1.8%) of macrophages in SIVE lesions were present in the CNS before SIVE lesion formation. There was a 2.9-fold increase in SIVp28⁺ macrophages entering the CNS late compared with those entering early (Pá<á0.05). The rate of CD163⁺ macrophage recruitment to the CNS inversely correlated with time to death (Pá<á0.03) and increased with SIVE. In SIVE animals, soluble CD163 correlated with CD163⁺ macrophage recruitment (Pá=á0.02). Most perivascular macrophages that comprise SIVE lesions and multinucleated giant cells are present in the CNS early, before SIVE lesions are formed. Most SIV-infected macrophages traffic to the CNS terminally with AIDS.