BACKGROUND AND AIMS: Cerebral infarction in COVID-19 patients might be associated with a hypercoagulable state related to a systemic inflammatory response. Its diagnosis might be challenging. We present two critically ill patients with COVID-19 who presented acutely altered mental status as the main manifestation of multiple strokes. METHODS: Clinical presentation and diagnostic work-up of the patients. RESULTS: Two patients in their sixties were hospitalized with a bilateral pneumonia COVID-19. They developed respiratory failure and were admitted to ICU for mechanical ventilation and intense medical treatment. They were started on low-molecular-weight heparin since admission. Their laboratory results showed lymphopenia and increased levels of C-reactive protein and D-dimer. Case 1 developed hypofibrinogenemia and presented several cutaneous lesions with biopsy features of thrombotic vasculopathy. Case 2 was performed a CT pulmonary angiogram at ICU showing a bilateral pulmonary embolism. When waking up, both patients were conscious but with a remarkable global altered mental status without focal neurological deficits. A brain MRI revealed multiple acute bilateral ischemic lesions with areas of hemorrhagic transformation in both patients (case 1: affecting the left frontal and temporal lobes and both occipital lobes; case 2: affecting both frontal and left occipital lobes). Cardioembolic source and acquired antiphospholipid syndrome were ruled out. COVID-19-associated coagulopathy was suspected as the possible main etiology of the strokes. CONCLUSION: Acutely altered mental status might be the main manifestation of multiple brain infarctions in critically ill COVID-19 patients. It should be specially considered in those with suspected COVID-19-associated coagulopathy. Full-dose anticoagulation and clinical-radiological monitoring might reduce their neurological consequences.