Vaccine- induced immune thrombocytopenia and thrombosis (VITT) is a rare adverse event occurring after immunization with adenoviral vector-based vaccines against SARS-CoV-2. This life-threatening condition is characterized by thrombocytopenia, systemic activation of coagulation, and anti-platelet factor 4 antibodies, often resulting in extensive venous thrombosis. Arterial thrombosis is less common and mainly affects the aorta, peripheral arteries, heart, and brain. Several cases of ischemic stroke have been reported in VITT patients, frequently being associated with large vessel occlusion (LVO). Here, we present a case of aggressive VITT in a 46-year-old woman with a past mild SARS-CoV-2 infection, who was admitted with a left-middle cerebral artery (MCA) territory stroke and thrombocytopenia eight days after her first dose of the ChAdOx1 nCoV-19 vaccine. The patient developed a diffuse arterial thrombosis with concomitant thrombotic events in the intrahepatic portal branches. The patient’s clinical condition worsened rapidly due to a significant enlargement of the ischemic cerebral lesion in the left hemisphere, cerebral herniation, and incipient hydrocephalus requiring decompressive neurosurgery with an unfavorable outcome. Our observations may be indicative of a stroke variant in VITT and highlight the diverse clinical manifestations of the syndrome.