1. Excitotoxic and apoptotic mechanisms have been implicated in the pathophysiology of cerebral ischaemia. Both MK-801, an NMDA receptor antagonist, or peptide inhibitors of the caspase family (z-VAD.FMK and z-DEVD.FMK), protect mouse brain from ischaemic cell damage. In this study, we examined whether these drugs which act via distinct mechanisms, afford even greater neuroprotection when given in combination following 2 h MCA occlusion (filament model) and 18 h reperfusion. 2. Given alone as pretreatment, MK-801 (1, 3 and 5 mg kg(-1), but not 0.3 mg kg(-1), i.p.) decreased infarct size by 34-75%. When injected 1 h after occlusion and before reperfusion, 3 mg kg(-1) reduced injury but not when administered I h after reperfusion. 3. Pretreatment with a subthreshold dose of MK-801 (0.3 mg kg(-1)) plus a subthreshold dose of z-VAD.FMK (27 ng) or z-DEVD (80 ng) significantly decreased infarct size by 29 and 30%, respectively, and enhanced neurological function. 4. Administering a subthreshold dose of z-VAD.FMK (27 ng) or z-DEVD.FMK (80 ng) as pretreatment extended the time window for MK-801 (3 mg kg(-1)) by 2 h from 1 h before reperfusion to at least 1 h after reperfusion. 5. Pretreating with a subthreshold dose of MK-801 (0.3 mg kg(-1)) extended the time window for z-DEVD.FMK (480 ng) from 1 h after reperfusion to at least 3 h after reperfusion. 6. We conclude that caspase inhibitors which putatively block apoptotic cell death and inhibit cytokine production and the NMDA antagonist MK-801 act synergistically and prolong their respective therapeutic windows in cerebral ischaemia.