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BACKGROUND Recently, extravascular fibrinogen leakage has emerged as a potential trigger of local neuroinflammation in the CNS. In the animal models of MS, fibrin depletion decreased neuroinflammation and neurodegeneration. The role of fibrinolytic therapy in patients with MS has not been studied. OBJECTIVE To describe a unique case of rapid clinical improvement after fibrinolytic therapy in a patient with MS and symptomatic acute demyelinating lesion. METHODS The MS patient with acute right-sided weakness was thought to have a stroke and received intravenous recombinant tissue plasminogen activator (rtPA). Serial neurological exams and MRI were performed. RESULTS/CONCLUSION In 5.4 hours after rtPA administration, NIH Stroke Scale score improved from 9 to 1, and this improvement persisted until 21 hours from symptom onset, approximate duration of rtPA action. Brain MRI revealed a symptomatic acute demyelinating lesion with restricted diffusion. We suggest that fibrin may serve as a potential therapeutic target in a subset of people with MS.