Since both glutamate excitotoxicity and inflammatory responses have been implicated in ischaemic neuronal death, we questioned whether joint inhibition of both processes would be more neuroprotective than either on its own. Therefore we assessed the effects of combined inhibition of both glutamate release (with a use-dependant sodium channel blocker, 619C89) and inflammatory processes (with a platelet-activating factor (PAF) receptor antagonist, BB-823) on the degree of motor deficit and the extent of cerebral (cortical and sub-cortical grey matter) infarction produced by middle cerebral artery occlusion (MCAO) in the rat, and compared results to appropriate single agent, vehicle and positive controls. The combination of both agents produced the greatest reduction in motor deficit, but the effect was only significant (p<0.05) acutely (4 to 6 hours post-MCAO). The extent of cortical infarction at 24 hours post-MCAO was significantly reduced in all experimental groups compared to vehicle-controls (p<0.05) and the greatest reduction occurred in the combination group (55%), though it was not significantly better than either of the single agent groups. Similarly the greatest reduction in sub-cortical infarction was in the combination group, but this was also not significantly better than the single agents. The results of this novel combination of pharmacological interventions suggest that inhibition of both glutamate excitotoxicity and inflammatory responses afforded an overall enhanced, if modest, neuroprotective effect, compared to inhibition of either process alone. The possible mechanisms involved are discussed, but warrant further clarification before therapeutic strategies are developed.