A serine protease activated protein C has been shown to be a powerful neuroprotectant in stressed neurons and in hypoxic brain endothelium. In a clinically relevant model of embolic stroke in rodents, we now show that administration of activated protein C alone or in combination with tissue plasminogen activator, or both, 4 hours after embolic stroke improves the functional outcome and reduces brain infarction within 7 days of stroke. In contrast, tissue plasminogen activator alone was not protective. Thus, activated protein C may be useful as a new stand‐alone therapy for clinical stroke and to extend the time window of thrombolytic therapy. Ann Neurol 2005;58:474–477