Introduction Mechanical thrombectomy for large vessel occlusion in the anterior circulation has been shown to be beneficial. The question of whether this technique is safe and effective in the distal vasculature remains unanswered. We wanted to compare outcome data from mechanical thrombectomy of M2 branches of the middle cerebral artery (MCA) with those of the M1 segment, and better understand the clinical predictors of these M2 occlusions. Methods A retrospective analysis was performed of data prospectively collected between January 2017 and July 2021 from patients with acute ischemic stroke undergoing mechanical thrombectomy of isolated M1 or M2 branches of the MCA. Results 350 patients were identified, 287 with M1 and 63 with M2 occlusions. Mean age was 70.71 ± 12.55 and 75.21 ± 10.21 years, respectively (p = 0.0083). Baseline Alberta Stroke Program Computed Tomography (ASPECT) score was worse in the M1 cohort (7.68 ± 1.73 vs. 8.32 ± 1.54; p = 0.0079), while there was no significant difference in National Institutes of Health Stroke Scale (NIHSS) scores. No statistical disparity existed in mean procedure duration for each cohort; fewer thrombectomy attempts were required in the M2 cohort (2.01 vs. 1.63; p = 0.0478). There was no statistical difference in total time to recanalization (559.19 vs. 629.97, p = 0.2506). Similar rates of successful reperfusion were observed (Thrombolysis in Ischaemic Stroke score [TICI] ≥ 2b 80.84% vs. 71.43% p = 0.1221). Good outcome (modified Rankin scale ≤ 2) was 56.10 in M1 occlusions and 63.49% on M2 groups. Intracranial haemorrhage rates were similar. Conclusions M2 thrombectomy is safe and a significant proportion of patients achieve a good clinical outcome. Advanced age, atrial fibrillation and previous treatment with anticoagulants were predictors for poor outcome. Good outcome was achieved when effective recanalization was obtained.