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Background: Thrombotic thrombocytopenic purpura (TTP) considers a rare cause of ischemic stroke (IS). We reported a case of a newly diagnosed patient with acquired immune-mediated TTP (iTTP), in whom two IS events developed during 48 h., Case Presentation: A 59-year-old diabetic male was presented to the hospital 24 h after symptoms onset, including left hemiparesis, dysarthria, and decreased consciousness. A brain CT scan was performed with the suspicion of acute IS, indicating infarct lesions in the right middle cerebral artery (MCA) territory. The patient was not eligible for thrombolytic therapy due to admission delay. Over the next 24 h, the patient's neurological condition deteriorated, and the second brain CT scan showed new ischemic lesions in the left MCA territory. Initial laboratory evaluation indicated thrombocytopenia without evidence of anemia. However, in the following days, thrombocytopenia progressed, and microangiopathic hemolytic anemia (MAHA) developed. The ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity and inhibitors assay confirmed the diagnosis of iTTP. The patient underwent plasma exchange activity and inhibitors assay confirmed the diagnosis of iTTP. The patient underwent and pulse IV methylprednisolone. Rituximab was also added due to the refractory course of the disease. After a prolonged hospital course, he had considerable neurologic recovery and was discharged., Conclusions: Clinicians should consider two points. First, TTP should be considered in any patient presenting with IS and having thrombocytopenia or anemia without other symptoms of TTP. Second, worsening the patient's condition during hospitalization may indicate a new stroke and should be investigated immediately., (© 2023. The Author(s).)