The neuroprotective activity of two systemically administered N-methyl-D-aspartate (NMDA) receptor antagonists, ketamine and MK-801, were investigated in a long-term recovery model of near-complete forebrain ischemia in the rat. Doses of each drug were chosen on the basis of the known degree and time course of NMDA antagonism seen in vivo after their systemic administration. Ketamine, administered at a dose of 20 mg.kg-1 iv, either immediately before or shortly after the 10-min ischemic period, failed to lessen neuronal damage in the selectively vulnerable hippocampal CA1 region. Increasing doses of ketamine administered over an increasing length of time in the postischemic period, however, did provide significant protection. MK-801 0.25 or 0.5 mg.kg-1 iv administered before ischemia also resulted in significant protection. The results support the proposal that NMDA receptor-mediated events may contribute to neuronal damage in selectively vulnerable regions of the central nervous system after ischemia.