BACKGROUND AND PURPOSE: In large artery occlusion stroke, both intravenous (IV) tPA (tissue-type plasminogen activator) and endovascular stroke treatment (EST) are standard-of-care. It is unknown how often tPA causes distal embolization, in which a procedurally accessible large artery occlusion is converted to a more distal and potentially inaccessible occlusion. METHODS: We analyzed data from a decentralized stroke telemedicine program in an integrated healthcare delivery system covering 21 hospitals, with 2 high-volume EST centers. We captured all cases sent for EST and examined the relationship between IV tPA administration and the rate of distal embolization, the rate of target recanalization (modified Treatment in Cerebral Infarction scale 2b/3), clinical improvement before EST, and short-term and long-term clinical outcomes. RESULTS: Distal embolization before EST was quite common (63/314 [20.1%]) and occurred more often after IV tPA before EST (57/229 [24.9%]) than among those not receiving IV tPA (6/85 [7.1%]; P<0.001). Distal embolization was associated with an inability to attempt EST: after distal embolization, 26/63 (41.3%) could not have attempted EST because of the new clot location, while in cases without distal embolization, only 8/249 (3.2%) were unable to have attempted EST (P<0.001). Among patients who received IV tPA, 13/242 (5.4%) had sufficient symptom improvement that a catheter angiogram was not performed; 6/342 (2.5%) had improvement to within 2 points of their baseline NIHSS. At catheter angiogram, 2/229 (0.9%) of patients who had received tPA had complete recanalization without distal embolization. Both IV tPA and EST recanalization were associated with improved long-term outcome. CONCLUSIONS: IV tPA administration before EST for large artery occlusion is associated with distal embolization, which in turn may reduce the chance that EST can be attempted and recanalization achieved. At the same time, some IV tPA-treated patients show symptomatic improvement and complete recanalization. Because IV tPA is associated with both distal embolization and improved long-term clinical outcome, there is a need for prospective clinical trials testing the net benefit or harm of IV tPA before EST.