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Purpose Endovascular treatment (ET) in occlusions of the M1- and proximal M2-segment of the middle cerebral artery (MCA) is an established procedure. In contrast, ET in distal M2-occlusions has not been sufficiently evaluated yet. The purpose of this study was to assess relevant parameters for clinical outcome, efficacy, and safety of patients undergoing ET in M1-, proximal M2-, and distal M2-occlusions. Methods One hundred seventy-four patients undergoing ET in acute ischemic stroke with an occlusion of the M1- or M2-segment of the MCA were enrolled prospectively. Non-parametric analysis of variance in 3-month mRS, TICI scale, and complication rates were performed with Kruskal–Wallis test between M1- and proximal and distal M2-occlusions. Subsequent pairwise group comparisons were calculated using Mann–Whitney U-tests. Binary logistic regression models were calculated for each occlusion site. Results There were no significant group differences in 3-month mRS, mTICI scale, or complication rates between M1- and M2-occlusions nor between proximal and distal M2-occlusions. Binary logistic regression in patients with M1-occlusions showed a substantial explanation of variance (NR2=0.35). NIHSS ( p=0.009) and Maas Score as parameter for collateralization ( p=0.01) appeared as significant contributing parameters. Binary logistic regression in M2-occlusions showed a high explanation of variance (NR2=0.50) of mRS but no significant factors. Conclusions Clinical outcome and procedural safety of patients with M2-occlusions undergoing ET are comparable to those of patients with M1-occlusions. Clinical outcome of patients with M1-occlusions undergoing ET is primarily influenced by the initial neurological deficit and the collateralization of the occlusions. By contrast, clinical outcome in patients with M2-occlusions undergoing ET is more multifactorial.