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Background Endovascular therapy within 24 hours of stroke onset is effective and safe, but successful recanalization does not always give favorable outcomes. Ischemic postconditioning (IPostC), a reperfusion strategy with potential neuroprotective effects, has been extensively studied in preclinical models, but its impact in humans remains unclear. Building on a previous dose escalation study, we aimed to investigate the effect of in situ IPostC on infarct volume in patients with acute ischemic stroke following mechanical thrombectomy.Methods This prospective, externally controlled, non-randomized trial compared in situ IPostC (four cycles of 2 min of occlusion/2 min of release) plus thrombectomy with contemporaneous external controls receiving thrombectomy alone. Propensity score matching (PSM) minimized selection bias. The primary outcome was infarct volume at 72 hours post-thrombectomy. Deep infarct volume was also compared in post hoc analyses. Peripheral blood was collected 24 hours post-procedure to assess leukocyte populations, with mononuclear cell subsets characterized by flow cytometry. Serum inflammatory biomarkers were also measured in both groups.Results After 1:1 PSM, 19 patients per group were analyzed. The IPostC group showed significantly less deep infarct volume progression (median 2.3 vs 4.7 mL; P=0.045), lower interleukin 6 levels (median 26.4 vs 32.6 pg/mL; P=0.032), higher Th/CTL ratios (median 2.04 vs 1.65; P<0.01), and reduced natural killer cell proportions (median 1.10% vs 1.68%; P=0.047).Conclusions In situ IPostC following thrombectomy for large vessel occlusion stroke may be associated with reduced deep infarct volume progression and favorable immunomodulatory effects, warranting further validation in phase II trials.Trial registration ClinicalTrials.gov NCT05909982.