The efficacy of MK-801, an N-methyl-D-aspartate receptor antagonist, was evaluated in a rat model of retinal ischemia induced by elevated intraocular pressure. Intraperitoneal injection of MK-801 at 0, 1, 3 and 10 mg/kg was given immediately after reperfusion. At 7 days after reperfusion, the inner retinal thickness, as measured from histologic sections of the retinas, of the 10 mg/kg treated group showed significant beneficial effect, while the other doses had no significant effect. Retinal ganglion cell counts on flat preparations of the retinas showed a beneficial dose dependent effect of MK-801 with the lowest dose showing no effect, 3 mg/kg showing marginal effects and 10 mg/kg showing significant effects. Intravitreal infusion of MK-801 during the ischemic period suppressed ischemia/reperfusion-induced internucleosomal DNA fragmentation measured at 18 hours after the insult as well as retinal tissue responses measured at 7 days. These findings suggested that the NMDA receptors may have an important role in ischemia-reperfusion insult as well as in mediating ischemia-induced apoptosis of retinal neurons. In addition, we demonstrated that pharmacological modulation of apoptotic cell death may affect the final tissue responses in vivo.