Background/purpose: The benefit of endovascular thrombectomy in acute ischemic stroke (AIS) therapy of proximal large vessel occlusions (LVO) is established. However, there are few prospective studies evaluating the use of a direct aspiration first pass technique in distal vessel occlusions. This post hoc analysis of the PROMISE study examines the safety and effectiveness of the Penumbra System with the ACE68 and ACE64 Reperfusion Catheters for aspiration thrombectomy in the M1 and M2 segments of the middle cerebral artery. Methods: PROMISE is a prospective, multicenter study that enrolled 204 patients with anterior circulation LVO AIS-treated frontline with ACE68/ACE64 catheters. We compared clinical and angiographic outcomes, complications, and mortality in patients with M1 and M2 occlusions. The association of M1 and M2 location and functional independence or mTICI 2b-3 reperfusion was described in univariable and multivariable analyses. Results: One hundred sixty-one patients (124 M1 and 37 M2 locations) met the study criteria. Post procedure mTICI 2b-3 reperfusion (93% vs. 92%, p = 1.00), functional independence (57% vs. 70%, p = 0.18), symptomatic intracranial hemorrhage (1.6% vs. 2.7%, p = 0.55), device- or procedure-related serious adverse events at 30 days (4.0% vs. 8.1%, p = 0.39), and mortality at 90 days (6.6% vs. 2.7%, p = 0.69) were comparable between M1 and M2 occlusions. In multivariable analysis, lower age, lower baseline NIHSS, and shorter time from onset to admission were independent predictors of functional independence. Conclusions: For frontline aspiration thrombectomy of stroke, use of large-bore ACE68/ACE64 catheters for treatment of M2 occlusions appeared as safe and effective as for M1 occlusions.