To examine early cellular changes, including astrocyte reactivity and microglial activation, in the central nervous system (CNS) after unilateral optic nerve transection (ONT) or ocular hypertension (OHT) in monkeys. Unilateral ONT or OHT was achieved in monkeys for periods ranging from two weeks to two months in duration. After intracardial perfusion, sections of the lateral geniculate nucleus (LGN) and visual cortex (V1) were examined by immunohistochemistry for glial fibrillary acidic protein (GFAP) and CD11b, a subunit of the complement 3 receptor and marker of macrophage and microglia cells (MAC-1). Alternate serial sections were evaluated by cytochrome oxidase (CO) histochemistry to assess metabolic activity. Both ONT and OHT caused a reduction in metabolic activity in the treated eye layers of the LGN and V1. GFAP and MAC-1 immunoreactivities were elevated in spatial register with the treated eye layers of the LGN and V1 in ONT animals. In the OHT animals, GFAP, but not MAC-1, immunoreactivity was elevated in spatial register with the treated eye layers of LGN and V1. Thus, during the first weeks after OHT or ONT, loss of metabolic activity was accompanied by astrocyte and microglial activation in the ONT group and astrocyte activation in the OHT animals. These results suggest that unilateral OHT or ONT triggers separate signaling pathways that promote differential activation of CNS glial populations. Astrocyte reactivity was present in all brains studied and demonstrates the loss of metabolic activity is accompanied by increased GFAP immunoreactivity. Microglial activation was only observed in ONT brains. The lack of microglial activation as late as two months following OHT may represent a time window for early treatment to prevent long-term neuronal loss in the CNS after OHT.