INTRODUCTION: Current treatments for acute ischemic stroke are approved based on time of onset, providing a dilemma for stroke patients with unknown onset time. About 25% of patients present as wake-up strokes (WUS). Our aim was to identify characteristics associated with the clinical outcomes of WUS patients receiving acute revascularization therapies. METHODS: We retrospectively reviewed medical records of consecutive patients with ischemic stroke who received treatment at a large academic medical center from 1994-2014. We identified patients with symptoms upon awakening and those with indefinite time of onset presenting within 24 hours of last known normal time. Demographics, NIHSS, diffusion-weighted imaging-based Alberta Stroke Program Early Computed Tomography Score (DWI-ASPECTS), treatment, and modified Rankin Scale (mRS) at 90-day follow-up were obtained. A good outcome was defined as 90-day mRS 0-2. RESULTS: Patients with unknown stroke onset time comprised 25.6% (90/351) of acute strokes treated in our series. Seventy-two were WUS, and 18 were indefinite time of onset not upon awakening. Median age was 70.5 (range 2-92), median NIHSS 13 (range 2-27), and median DWI-ASPECTS 8 (range 1-10). Large vessel occlusions were as follows: 39 M1 middle cerebral artery (MCA), 16 M2 MCA, 9 intracranial internal carotid artery (ICA), 8 basilar artery, 6 extracranial ICA, 2 M3 MCA, 2 distal MCA, 1 A2 anterior cerebral artery, 1 posterior cerebral artery, and 1 vertebral artery. Five cases did not have an occlusion. Forty-six were treated with thrombectomy, 11 with IV thrombolysis, 14 IA thrombolysis, 10 IA thrombolysis + thrombectomy, 3 IV + IA thrombolysis, 5 IV thrombolysis + thrombectomy, and 1 IV + IA thrombolysis + thrombectomy. Sixty-one patients had MRI on initial evaluation, and 51 (77%) had DWI-ASPECTS≥7. Of those, 16 (31.4%) had a good outcome at follow-up. Only 1 patient with DWI-ASPECTS<7 had good outcome, and 14/33 patients with DWI-ASPECTS≥7 had good outcome (p=0.04). Lower age (65 vs 74, p=0.03) was a predictor of good outcome at follow-up. CONCLUSIONS: Patients with anterior circulation strokes with unknown onset time and DWI-ASPECTS≥7 have potential for good outcome with acute treatment.