Measurement of central nervous system (CNS) expression of the peripheral benzodiazepine receptor (PBR), a microglia and macrophage activation marker, by positron emission tomography (PET) would aid clinical management of human immunodeficiency virus (HIV)-infected patients. To evaluate the utility of examining PBR expression in the CNS as a cellular activation marker in HIV CNS disease, PBR levels were measured in frontal cortex of simian immunodeficiency virus (SIV)-infected macaques with encephalitis and uninfected animals via PK11195 ligand autoradiography. [³H]-(R)-PK11195 binding to both grey matter (P = .017) and white matter (P = .038) was significantly higher in animals with SIV encephalitis (n = 10) versus control animals (n = 3). When PK11195 binding was compared with other microglial/macrophage activation markers (obtained via quantitative image analysis), a strong, significant association was found for both HAM56 (P = .004) and KP-1 (anti-CD68; P = .006) immunostaining in white matter. In contrast, grey matter PK11195 binding did not correlate with HAM56 (P = .46), KP-1 (P = .06), or glial fibrillary acidic protein (GFAP) immunostaining for astrocytic activation (P = .09). The regional nature of these increases in activation within the brain illustrates the crucial need to focus functional neuroimaging analyses of HIV-infected individuals on subcortical white matter to assess activation of microglia and macrophages.