BACKGROUND AND PURPOSE: Standard selection criteria for revascularization therapy usually exclude patients with unclear-onset stroke. Our aim was to evaluate the efficacy and safety of revascularization therapy in patients with unclear-onset stroke in the anterior circulation and to identify the predictive factors for favorable clinical outcome. MATERIALS AND METHODS: We retrospectively analyzed 41 consecutive patients presenting with acute stroke with unknown time of onset treated by intravenous thrombolysis and/or mechanical thrombectomy. Only patients without well-developed fluid-attenuated inversion recovery changes of acute diffusion lesions on MR imaging were enrolled. Twenty-one patients were treated by intravenous thrombolysis; 19 received, simultaneously, intravenous thrombolysis and mechanical thrombectomy (as a bridging therapy); and 1 patient, endovascular therapy alone. Clinical outcome was evaluated at 90 days by using the mRS. Mortality and symptomatic intracranial hemorrhage were also reported. RESULTS: Median patient age was 72 years (range, 17-89 years). Mean initial NIHSS score was 14.5 ± 5.7. Successful recanalization (TICI 2b-3) was assessed in 61% of patients presenting with an arterial occlusion, symptomatic intracranial hemorrhage occurred in 2 patients (4.9%), and 3 (7.3%) patients died. After 90 days, favorable outcome (mRS 0-2) was observed in 25 (61%) patients. Following multivariate analysis, initial NIHSS score (OR, 1.43; 95% CI, 1.13-1.82; P = .003) and bridging therapy (OR, 37.92; 95% CI, 2.43-591.35; P = .009) were independently associated with a favorable outcome at 3 months. CONCLUSIONS: The study demonstrates the safety and good clinical outcome of acute recanalization therapy in patients with acute stroke in the anterior circulation and an unknown time of onset and a DWI/FLAIR mismatch on imaging. Moreover, bridging therapy versus intravenous thrombolysis alone was independently associated with favorable outcome at 3 months.