BACKGROUND: We aim to assess the efficacy of rapid local ischemic postconditioning (RL-IPostC) following successful reperfusion in patients with acute ischemic stroke with anterior circulation large vessel occlusion who underwent endovascular thrombectomy. METHODS: We conducted an ambidirectional cohort study with 78 prospectively enrolled patients with RL-IPostC and endovascular thrombectomy and 129 retrospectively enrolled patients with endovascular thrombectomy. The RL-IPostC procedure involved 5 cycles of 15-s balloon inflation and deflation in the ipsilateral internal carotid artery. The primary outcome was functional independence, defined as a modified Rankin Scale score of 0 to 2. Secondary outcomes included excellent outcomes (modified Rankin Scale score, 0–1) and early therapeutic response. Imaging outcomes involved infarct volume changes and cerebral edema measurements. Outcomes were compared with postpropensity score matching (1:1) and assessed using univariable and multivariable regression models. RESULTS: In the matched cohort of 136 patients (mean age, 71±14 years; 70 men [51%]), RL-IPostC was associated with a higher rate of functional independence (adjusted odds ratio, 2.47 [95% CI, 1.10–5.68]; P =0.030). The RL-IPostC group exhibited significantly reduced infarct volumes at 24 hours (difference, −12.2 [95% CI, −23.9 to −0.53]; P =0.041) and less infarct growth (difference, −12.2 [95% CI, −23.9 to −0.45]; P =0.042). Furthermore, RL-IPostC correlated with lower increases in net water uptake (difference, −0.04 [95% CI, −0.07 to −0.01]; P =0.018), lower decrease cerebrospinal fluid volume (difference, −7.75 [95% CI, −11.7 to −3.84]; P <0.001), and reduced midline shift at 24 hours (difference, −1.39 [95% CI, −2.48 to −0.30]; P =0.013). CONCLUSIONS: RL-IPostC tends to promote functional independence and reduces infarct growth and cerebral edema in patients with acute ischemic stroke post-reperfusion.