Intravenous tissue plasminogen activator (tPA) is standard treatment for eligible patients with acute ischemic stroke, but may be less effective for very severe strokes caused by proximal intracranial artery occlusions. We report the case of a woman with a devastating stroke who recovered completely following emergency revascularization of an occluded proximal middle cerebral artery using a novel treatment approach that combines both intravenous (i.v.) and intra-arterial (IA) tPA. This case illustrates the potential value of the combined i.v.-IA thrombolytic approach, which is an emerging investigational treatment strategy for selected patients with severe acute ischemic stroke.