BACKGROUND: It is acknowledged that penumbra can exist beyond 24 h after stroke onset. AIMS: The aim of this study was to explore the association between penumbral persistence at 24-72 h and clinical outcomes in patients who did not achieve major reperfusion. METHODS: Eligible patients participating in the International Stroke Perfusion Imaging Registry with repeated 24-72 h perfusion imaging were retrospectively included in this study. Persistent penumbra was evaluated as the volume of hypoperfusion lesion on repeated perfusion imaging divided by infarct volume on the follow-up imaging at 24-72 h post arrival. Short-term clinical outcomes were defined as neurological deterioration at 24-72 h and modified Rankin Scale (mRS) 0-2 at discharge. Long-term outcome was defined as mRS 0-2 at 3 months. The association between persistent penumbra and clinical outcomes was explored using multivariable-adjusted logistic regression models. RESULTS: A total number of 203 patients were included in this study. Persistent penumbra was associated with decreased odds of neurological deterioration at 24-72 h (multivariable-adjusted odds ratio (OR) = 0.3, 95% confidence interval (CI) = 0.1-0.8, p = 0.01) and increased odds of mRS 0-2 at 3 months (multivariable-adjusted OR = 2.7, 95% CI = 1.1-6.8, p = 0.03). Persistent penumbra was not associated with mRS 0-2 at discharge (multivariable-adjusted OR = 2.5, 95% CI = 0.4-14.7, p = 0.30). CONCLUSIONS: Persistent penumbra in acute stroke patients without major reperfusion was generally associated with a better clinical outcome. This evidence suggested that there were patients with persistent hemodynamic support, for whom major reperfusion might not be pivotal to achieve a good clinical outcome. How to identify these patients and what treatment strategy can be made to stabilize the hemodynamics need future investigation. DATA ACCESS STATEMENT: Anonymized data not published within this article will be made available at the request of qualified investigators whose proposal of data use has been approved by an independent review committee.