The objective of this study was to determine the clinical features, angiographic findings, and response to treatment with thrombolytic therapy in patients with ischemic stroke caused by acute occlusion of the distal internal carotid artery. This is a retrospective case series from a prospectively collected stroke database for patients with acute internal carotid occlusion presenting within 6 hours of stroke onset to evaluate safety, feasibility, and response to thrombolytic therapy. The University Hospital-based brain attack database was reviewed over a 5-year period. Demographics, clinical features, stroke mechanisms, severity, imaging findings, type of thrombolysis, treatment responses, mortality, and long-term outcome using modified Rankin Scale and Barthel Index were determined. The short-term outcome was assessed using the National Institutes of Health Stroke Scale (NIHSS). Acute thrombolytic therapy was administered using recombinant tissue plasminogen activator or urokinase given intra-arterially or in combination with intravenous (IV) routes. Two hundred seven patients treated with thrombolysis between 1995 and 2000 were reviewed, and of these, 101 were studied with cerebral angiography. Eighteen patients were identified with acute ischemic stroke and ipsilateral occlusion of the distal internal carotid artery. Time to treatment was the most powerful predictor of response to thrombolytic therapy (P<0.001). The response to therapy also correlated well with the severity of the initial clinical deficit as judged by the NIHSS (P<0.001). There was no difference in recanalization rate, symptomatic hemorrhage, and NIHSS for IV/intra-arterial (IA) versus IA alone (P=NS). Complete angiographic recanalization was accomplished in 80% of those who received combined IV/IA thrombolysis and in 62% of those who received IA therapy (P=NS). Those with distal occlusions extending to the middle and anterior cerebral arteries were the least likely to respond to thrombolysis. Symptomatic intracerebral hemorrhage occurred in 20% of the patients receiving IV/IA therapy, and in 15% of the IA only (P=NS). At 24 hours, the NIHSS dropped by 3 points in the IA group and 4 points in the IV/IA group (P=NS). Mild disability with independence was found in 77% of the survivors at 3-month follow-up. The mortality rate was 50% in this group despite thrombolysis. Thrombolytic therapy using a combination of IV and IA routes and using the IA-only route may be effective in improving outcome for the patients suffering from occlusion of the distal internal carotid artery. Shorter intervals between onset and treatment seem to be correlated with higher rate of recanalization and improved outcome.