Introduction: In patients with large core ischemic stroke, potential heterogeneity in EVT treatment effect based on underlying etiology is an important question. We explored differences in clinical outcomes and successful recanalization rates between EVT and MM. Methods: From SELECT2 randomized clinical trial, patients were categorized based on Stroke etiology: Large-artery atherosclerosis (LAA), Cardioembolism (CE), Stroke of other determined etiology (SOE), and Stroke of undetermined etiology (SUE). Procedure success, clinical outcomes and EVT treatment effect was compared based on stroke etiology. Results: Cardioembolic stroke was most frequently observed etiology across the trial (41%), followed by stroke of undetermined etiology (29%), large artery atherosclerosis (23%) and stroke of other determined etiology (6%). Proportion of patients achieving successful reperfusion (mTICI 2b-3) after EVT differed significantly across the categories (CE: 87%, LAA: 82%, SOE: 73%, SUE: 66%, p=0.040). However, treatment effect estimates favored EVT across categories of stroke etiology without significant heterogeneity - CE (ref): aGenOR: 1.83 (1.30-2.59) vs LAA: aGenOR: 2.04 (1.24-3.37), p-int: 0.87 vs SOE: aGenOR: 2.06 (0.80-5.28), p-int: 0.79 vs SUE: aGenOR: 1.20 (0.77-1.88), p-int: 0.17. Conclusion: In patients with large core ischemic stroke, proportion of patients achieving successful reperfusion differed based on stroke etiology. However, EVT was associated with better outcomes without evidence of significant heterogeneity. Further optimization of procedure techniques may help improve successful reperfusion rates and clinical outcomes in patients with SUE. Clinicaltrials.gov registration: NCT03876457