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Background Intraprocedural antiplatelet therapy is commonly used during mechanical thrombectomy (MT) for middle cerebral artery (MCA) stroke, particularly when adjunctive angioplasty or stenting is required. Cangrelor, a direct-acting intravenous P2Y12 receptor antagonist, offers immediate onset, predictable platelet inhibition, and rapid offset, while eptifibatide (GP IIb/IIIa inhibitor) provides broader platelet inhibition with longer duration. We aimed to compare clinical outcomes between these agents in MCA stroke patients undergoing MT.Methods We conducted a retrospective cohort study using the TriNetX Research Network (113 healthcare organizations, January 2016 to January 2026). Adults with MCA stroke (ICD-10-CM: I63.31, I63.41, I63.51) who underwent MT and received concomitant intravenous cangrelor or eptifibatide on the day of or within 1 day following the procedure were identified. Documentation of NIHSS score was required; posterior circulation strokes were excluded. Propensity score matching (1:1 nearest-neighbor) balanced demographics, comorbidities, stroke severity categories, intracranial hemorrhage history, stenting/angioplasty procedures, thrombolytics, and antiplatelet medications. Primary outcomes included major bleeding, intracranial hemorrhage, and decompressive hemicraniectomy. Secondary outcomes included recurrent stroke at 1-6 and 1-24 months, prolonged ICU stay, mortality, and functional dependency at 1-90 and 91-180 days. Prespecified subgroup analysis stratified patients by adjunctive intracranial or cervical angioplasty/stenting.Results Of 980 eligible patients (cangrelor 407; eptifibatide 573), propensity score matching yielded 302 pairs with excellent covariate balance (all SMD 0.07 or less). Matched cohorts had mean age 67 years, 80% white, 41% female, with similar stroke severity distribution (36% NIHSS 0-9; 50% NIHSS 10-18; 31% NIHSS 20-29). In the overall matched cohort, no significant differences were observed in major bleeding (18.9% vs 24.5%; HR 0.74, 95% CI 0.53-1.05, p=0.08), ICH (17.9% vs 22.5%; HR 0.77, 95% CI 0.54-1.10, p=0.14), decompressive hemicraniectomy (21.9% vs 26.8%; HR 0.79, p=0.13), mortality (17.2% vs 14.9%; HR 1.13, p=0.55), or functional dependency within 90 days (19.9% vs 23.2%; HR 0.80, p=0.21). However, in the angioplasty/stenting subgroup (98 pairs), cangrelor was associated with significantly lower major bleeding (15.3% vs 26.5%; HR 0.53, 95% CI 0.28-1.01, p=0.047), ICH (14.3% vs 25.5%; HR 0.52, p=0.04), decompressive hemicraniectomy (17.3% vs 31.6%; HR 0.52, p=0.02), and functional dependency (18.4% vs 31.6%; HR 0.50, p=0.02), but higher recurrent stroke at 1-24 months (32.7% vs 11.2%; HR 2.57, 95% CI 1.30-5.11, p<0.01). No significant outcome differences were observed in patients without angioplasty/stenting.Conclusion Cangrelor and eptifibatide demonstrated comparable overall outcomes in MCA stroke patients undergoing MT. Among patients requiring angioplasty/stenting, cangrelor was associated with reduced hemorrhagic complications but increased recurrent stroke, suggesting a complex hemorrhage-ischemia tradeoff requiring individualized antiplatelet selection.Disclosures M. Essibayi: None.