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Background and Purpose: Early reperfusion using tissue-type plasminogen activator is the only therapeutic agent to treat focal cerebral ischemia with proven efficacy in patients. Nevertheless, novel insights into the pathophysiology of neurons, glial cells, and the fate of the endothelium after stroke call for the use of new strategies to improve stroke treatment alone or in combination with tissue-type plasminogen activator-induced thrombolysis. Unfortunately, despite the plethora of drugs that display clear beneficial effects in animal models of experimental ischemia, their subsequent use in clinical trials has proven disappointing. As such, one is forced to consider that new animal models of focal cerebral ischemia may be required before clinical evaluation of a new molecule., Methods: In situ microinjection of purified murine thrombin was used to trigger a local clot formation in anesthetized mice. Cerebral blood velocity was measured continuously throughout the duration of the study. The efficiency of recombinant tissue-type plasminogen activator to induce thrombolysis and its subsequent effect on infarct volume were then measured., Results: In situ thrombin injection leads to a reproducible clot formation and cortical brain injury. Recombinant tissue-type plasminogen activator-induced thrombolysis reduced infarct volume by 36.8% when compared with untreated control mice., Conclusions: We describe an original and reproducible mouse model of in situ clot formation and reperfusion, which could be used to investigate new therapeutic strategies to improve stroke treatment.