IntroductionPreviously published data are conflicting regarding the ability of tenecteplase versus alteplase to produce early recanalization of an intracranial large vessel occlusion. We compared the performance of each thrombolytic in a stroke network. MethodsWe queried our prospectively collected code stroke registry for basilar, internal carotid, or proximal middle cerebral artery occlusion patients treated with intravenous thrombolysis from 11/17/2021-9/16/2023. The primary outcome was early recanalization, defined using angiographic or clinical criteria. Secondary and safety outcomes included 90-day functional independence and symptomatic intracranial hemorrhage. A multivariable regression analysis was performed to determine independent associations with the primary outcome. Results233 patients, with mean age 66.9 (16.6) years and median National Institutes of Health Stroke Scale score 15 (10-21), were included. One-hundred twenty-four of 233 (53.2%) patients were treated with alteplase while 109/233 (46.8%) were treated with tenecteplase. Endovascular thrombectomy was performed in 82% of subjects. Early recanalization rates were similar between the groups (alteplase 22.6%, tenecteplase 14.7%; p=0.14), as were rates of 90-day independent neurological function, symptomatic intracranial hemorrhage, and mortality. Patients with an internal carotid artery occlusion or with higher presenting stroke severity were less likely to achieve early recanalization. ConclusionsTenecteplase and alteplase have similar rates of early recanalization, 90-day functional independence, and safety outcomes in large vessel occlusion patients. Occlusion site and stroke severity predict response to thrombolysis. Future studies may investigate other factors associated with a positive response to thrombolytics as expanded treatment indications are explored.