Background: The characteristics and pathophysiological mechanisms involved in acute ischemic stroke in patients with COVID-19 infection have not been fully clarified. We prospectively studied the phenotypic and etiological features of acute stroke occurring in COVID-19 infection. Patients & methods: Within nine months starting from April-2020, the presence of COVID-19 infection was determined by thoracic CT and SARS-CoV-2 PCR in all acute stroke cases managed in a single tertiary center. Consecutive and prospective data on vascular risk factors/comorbidities, in-hospital quality metrics, discharge outcomes, etiological subclassification and blood markers of thrombosis / inflammation were compared in 44 COVID-19 positive cases (37 acute ischemic stroke, 5 TIA, 2 intracerebral hematoma) and 509 COVID-19 negative patients (355 ischemic, 105 TIA, 44 hematoma and 5 stroke mimic). Results: COVID-19 positive patients had more severe strokes, delayed hospital admission, longer hospital stay, higher mortality rates, but had similar vascular risk factors/comorbidities frequency, thrombolysis/thrombectomy utilization rates, metrics, and stroke etiological subtype. They had significantly higher CRP, fibrinogen, ferritin, leukocyte count and lower lymphocyte count. No difference was detected in aPTT, INR, D-dimer, platelet, hemoglobin, homocysteine levels and ANA, anti-dsDNA antibody and ENA panel positivity rates. Anti-phospholipid antibodies have been studied in 70% of COVID-19 positive and all cryptogenic patients, but were never found positive. Tests for coagulation factor levels and hereditary thrombophilia did not show major thrombophilia in any of the stroke patients with COVID-19. Conclusion: We documented that there is no significant difference in etiological spectrum in acute stroke patients with COVID-19 infection. In addition, cryptogenic stroke and antiphospholipid antibody positivity rates did not increase. (c) 2021 Elsevier Inc. All rights reserved.