Background: Hemorrhagic transformation (HT) is a major complication of acute ischemic stroke, potentially associated with clinical deterioration. We attempted to identify risk factors and evaluated clinical relevance of minor and major HTs following endovascular thrombectomy (ET) in isolated middle cerebral artery (MCA) occlusions. Methods: This is a retrospective single-center analysis of 409 patients with isolated MCA occlusion treated with ET. Patients' and procedural characteristics, severity of HT according to the European Cooperative Acute Stroke Study criteria, and clinical outcomes were analyzed. Multivariate logistic regression models with standard retention criteria (p < 0.1) were used to determine risk factors and clinical relevance of HT. Results are shown as adjusted OR (aOR) and respective 95% CIs. Good neurologic short-term outcome was defined as National Institutes of Health Stroke Scale (NIHSS) score <5 at the day of discharge. Results: Of 299 patients included, hemorrhagic infarction (HI) was detected in 87 patients, while 13 patients developed parenchymal hematoma (PH). Higher age (aOR 0.970, 95% CI 0.947-0.993, p = 0.012), eligibility for intravenous recombinant tissue plasminogen activator (IV rtPA; aOR 0.512, 95% CI 0.267-0.982, p = 0.044), and complete recanalization (TICI 3, aOR 0.408, 95% CI 0.210-0.789, p = 0.008) were associated with a lower risk of HI. Risk factors for HI included higher admission NIHSS score (aOR 1.080, 95% CI 1.010-1.153, p = 0.024) and higher admission glucose levels (aOR 1.493, 95% CI 1.170-1.904, p = 0.001). Further, female sex tended to be associated with a lower risk of HI (aOR 0.601, 95% CI 0.316-1.143, p = 0.121), while a statistical trend was observable for proximal MCA occlusion (aOR 1.856, 95% CI 0.945-3.646, p = 0.073) and a history of hypertension (aOR 2.176, 95% CI 0.932-5.080, p = 0.072) to increase risk of HI. Longer intervals from symptom onset to first digital subtraction angiography runs (aOR 1.013, 95% CI 1.003-1.022, p = 0.009), lower preinterventional Alberta Stroke Program Early CT score (aOR 0.536, 95% CI 0.307-0.936, p = 0.028) and wake-up stroke (aOR 18.540, 95% CI 1.352-254.276, p = 0.029) were associated with PH. Both, PH and HI were independently associated with lower rates of good neurologic outcome (aOR 0.086, 95% CI 0.008-0.902, p = 0.041 and aOR 0.282, 95% CI 0.131-0.606, p = 0.001). Conclusion: Risk of HI following MCA occlusion and subsequent ET is mainly determined by factors influencing infarct severity. Good recanalization results seem to be protective against subsequent HI. Our results support the notion that occurrence of PH after ET is time dependent and risk increases with more extensive early ischemic damage. Both, HI and PH do not seem to be facilitated by bridging therapy with IV rtPA or the use of oral anticoagulants, but were independently associated with more severe neurologic disability. These results support the notion that HI is not a “benign” imaging sign.