Objectives. Thrombi responsible for large vessel occlusion (LVO) in the setting of acute ischemic stroke (AIS) are characterized by a low recanalization rate after intravenous thrombolysis. To test whether AIS thrombi have inherent common features that limit their susceptibility to thrombolysis, we analyzed the composition and ultrastructural organization of AIS thrombi causing LVO. Methods. A total of 199 endovascular thrombectomy-retrieved thrombi were analyzed by immunohistology, scanning electron microscopy (SEM), and subjected to ex vivo thrombolysis assay. The relationship between thrombus organization and thrombolysis resistance was further investigated in vitro using thrombus produced by recalcification of citrated whole blood. Results. SEM and immunohistology analyses revealed that, although AIS thrombus composition and organization was highly heterogeneous. AIS thrombi shared a common remarkable structural feature in the form of an outer shell made of densely compacted thrombus components including fibrin, von Willebrand factor, and aggregated platelets. In vitro thrombosis experiments using human blood indicated that platelets were essential to the formation of the thrombus outer shell. Finally, in both AIS and in vitro thrombi, the thrombus outer shell showed a decreased susceptibility to t-PA-mediated thrombolysis as compared to the thrombus inner core. Interpretation. Irrespective of their etiology and despite their heterogeneity, intracranial thrombi causing LVO have a core-shell structure that influences their susceptibility to thrombolysis.