• Thrombolytic therapy is likely to be effective in some patients with stroke, but further improvements may require combination treatment with neuroprotective agents that can be given rapidly with relative safety. We tested the effects of tissue plasminogen activator (t-PA) with the glutamate antagonist MK-801 or the calcium channel blocker nimodipine in an embolic stroke model. We found that MK-801, followed by t-PA, was more effective than t-PA alone in reducing neurologic damage. Nimodipine plus t-PA was not better than t-PA alone. Combined glutamate antagonist and thrombolytic therapy may provide increased efficacy and safety for stroke treatment.