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Background Distal and Medium vessel occlusions DMVO account for 25-40% of acute ischemic strokes. Recent randomized controlled trials found no benefit of endovascular therapy (EVT) in DMVO treatment, potentially due to the inclusion of older patients and those with milder clinical deficits. We aimed to determine if real-world outcomes differ from trial results when adjusted for baseline risk imbalances, and to evaluate the impact of procedural maturation over time.Methods This dual-phase study first performed a meta-analysis of the EVT arms from two recent trials (DISTAL and ESCAPE-MeVO) to establish a normative reference population. We then analyzed 501 consecutive DMVO patients treated between 2013-2024 from the Stroke Thrombectomy and Aneurysm Registry (STAR). Stochastic G-computation (1,000 Monte Carlo iterations) was employed to estimate a counterfactual scenario: The clinical outcomes the STAR registry would have achieved had its patients shared the same baseline risk profile of the pooled DMVO trial cohorts. Multivariable and longitudinal analyses were performed to identify patient and procedural predictors of good functional outcome (90-day modified Rankin Scale [mRS] 0-2. Sensitivity analysis was conducted on a contemporary cohort (2022-2024) from STAR corresponding to the active enrollment period of the comparator trials.Results STAR registry DMVO patients were significantly younger (mean 67.0 vs. 75.8 years, p < 0.001) but had higher baseline stroke severity (mean NIHSS 12.4 vs. 6.9, p < 0.001) than pooled trial estimates. Standardization of the STAR cohort to match trial profiles resulted in attenuated efficacy: Good functional outcome (mRS 0-2) decreased from 54.4% to 49.0%, and mortality increased from 17.2% to 20.0%. Longitudinal analysis (2013-2024) revealed significant increases in successful recanalization (67.4% to 82.0%, p < 0.001) and functional independence (34.8% to 51.2%, p = 0.002), alongside a decrease in median procedure time (66.5 to 37.4 minutes, p < 0.001). In the contemporary cohort (2022-2024), frontline contact aspiration emerged as an independent predictor of good functional outcome compared to combined techniques (aOR 1.51; 95% CI 1.28-2.19) and stent-retrievers (aOR 1.42; 95% CI 1.16-1.89).Conclusion Compared to a real-world multicenter stroke registry, the neutral results of recent DMVO EVT trials likely reflects enrollment biases toward older patients and those with mild deficits that may limit their potential for neurological improvement. Real-world data demonstrate that improvements in aspiration techniques and procedural efficiency significantly improve the likelihood of good functional outcomes in DMVO patients undergoing EVT.Disclosures R. Abo Kasem: None. E. Luther: None. D. Romano: None. O. Tanweer: None. C. Ogilvy: None. J. Kim: None. R. Crosa: None. I. Fragata: None. A. Polifka: None. F. Siddiqui: None. J. Mascitelli: None. I. Abecassis: None. D. Ding: None.Abstract O-005 Figure 1