Background and Purpose Therapeutic hypothermia improves outcomes in experimental stroke models, especially after ischemia-reperfusion injury. We investigated the clinical and radiological effects of therapeutic hypothermia in acute ischemic stroke patients after recanalization. Methods A prospective cohort study at 2 stroke centers was performed. We enrolled patients with acute ischemic stroke in the anterior circulation with an initial National Institutes of Health Stroke Scale 10 who had successful recanalization (thrombolysis in cerebral ischemia, 2b). Patients at center A underwent a mild hypothermia (34.5 degrees C) protocol, which included mechanical ventilation, and 48-hour hypothermia and 48-hour rewarming. Patients at center B were treated according to the guidelines without hypothermia. Cerebral edema, hemorrhagic transformation, good outcome (3-month modified Rankin Scale, 2), mortality, and safety profiles were compared. Potential variables at baseline and during the therapy were analyzed to evaluate for independent predictors of good outcome. Results The hypothermia group (n=39) had less cerebral edema (P=0.001), hemorrhagic transformation (P=0.016), and better outcome (P=0.017) compared with the normothermia group (n=36). Mortality, hemicraniectomy rate, and medical complications were not statistically different. After adjustment for potential confounders, therapeutic hypothermia (odds ratio, 3.0; 95% confidence interval, 1.0-8.9; P=0.047) and distal occlusion (odds ratio, 7.3; 95% confidence interval; 1.3-40.3; P=0.022) were the independent predictors for good outcome. Absence of cerebral edema (odds ratio, 5.4; 95% confidence interval, 1.6-18.2; P=0.006) and no medical complications (odds ratio, 9.3; 95% confidence interval, 2.2-39.9; P=0.003) were also independent predictors for good outcome during the therapy. Conclusions In patients with ischemic stroke, after successful recanalization, therapeutic hypothermia may reduce risk of cerebral edema and hemorrhagic transformation, and lead to improved clinical outcomes.