Simian immunodeficiency virus-infected macaques may develop encephalitis, a feature more commonly observed in macaques with rapid progressive disease than in those with conventional disease. In this report, an analysis of 2 conventional progressors with encephalitis is described. Phylogenetic analyses of viruses isolated from the cerebrospinal fluid and plasma of both macaques demonstrated compartmentalization. Furthermore, these viruses appear to have undergone adaptive evolution to preferentially replicate in their respective cell targets of monocyte-derived macrophages and peripheral blood mononuclear cells. A statistically significant loss of potential N-linked glycosylation sites in glycoprotein 160 was observed in viruses isolated from the central nervous system.