BACKGROUND: Intravenous alteplase for acute ischemic stroke is least efficacious for patients with proximal large-artery occlusions and clinically severe strokes. Intra-arterial therapy has the theoretical advantage of establishing a neurovascular diagnosis and high symptomatic artery patency rate but the disadvantage of requiring extra time and technical expertise. A combination of these two approaches may provide the best chance of improving outcome in severe acute ischemic stroke. We sought to assess the safety and feasibility of this approach. METHODS: This was a prospective, open-label study. Sequential patients arriving to our center within 3 hours of stroke onset who were treated with intravenous alteplase were screened for possible additional intra-arterial therapy using noninvasive neuroimaging. Clinical measures and outcomes were recorded prospectively. RESULTS: A total of 861 patients with ischemic stroke were admitted to Calgary hospitals during the study period. Eight patients over 21 months underwent a combined intravenous-intra-arterial approach. Six received intra-arterial alteplase and 1 underwent intracranial angioplasty; in a final patient, technical aspects prevented intra-arterial therapy. Early neurovascular and/or neurometabolic imaging identified the location of occlusion and tissue-at-risk (DWI-PWI mismatch) in all 8 patients. Two patients had a poor outcome, 1 patient suffered a significant groin hematoma, and there were no instances of symptomatic intracerebral hemorrhage. CONCLUSIONS: Intravenous followed by intra-arterial therapy is a promising approach to the treatment of severe acute ischemic stroke. Early noninvasive neurovascular and neurometabolic imaging is very helpful in choosing candidates for this type of therapy. On-going monitoring of alteplase-treated patients may allow the opportunity to perform rescue intra-arterial therapy.