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Introduction Vertebrobasilar tandem lesions (VBTLs) represent a high-mortality, anatomically complex subtype of posterior circulation stroke. While the efficacy of endovascular thrombectomy (EVT) for isolated basilar artery occlusion is now established, evidence regarding VBTLs is restricted to small cohorts comparing tandem lesions to isolated occlusions. To date, no study has compared EVT with medical management (MM) in this population. We aimed to evaluate the safety and efficacy of EVT versus MM for acute VBTLs.Methods In this multicenter cohort study utilizing a prospectively maintained database across 47 centers, we identified consecutive adults presenting with acute ischemic stroke due to VBTLs. Inclusion criteria were intracranial occlusion (V4 or basilar artery) with a tandem extracranial steno-occlusive lesion (V1-V3, >70%) and impaired distal flow, baseline NIHSS ≥6, and pc-ASPECTS ≥6. Patients were stratified by treatment (EVT vs. MM). The primary outcome was 90-day functional independence (mRS 0-3). Treatment effect was evaluated utilizing multivariable logistic regression, inverse probability of treatment weighting (IPTW), and 1:1 propensity score matching (PSM).Results Among 639 included patients (EVT n=435; MM n=204; median age 66 years), EVT was associated with significantly higher rates of 90-day mRS 0-3 across all analytical models: adjusted OR 9.19 (95% CI 5.14-16.41; p<0.0001), IPTW OR 6.38 (p<0.0001), and PSM OR 5.26 (p<0.0001). EVT profoundly reduced 90-day mortality (aOR 0.17; p<0.0001) and improved ordinal mRS shift (acOR 6.67; p<0.0001). Symptomatic intracranial hemorrhage (sICH) occurred more frequently in the EVT cohort (15.3% vs. 2.5%; aOR 6.06; p=0.001). After Bonferroni correction, baseline NIHSS emerged as the sole significant effect modifier (p-interaction=0.004); the treatment benefit of EVT was massively amplified in patients with severe deficits (NIHSS ≥16: OR 50.41) compared to those with NIHSS <16 (OR 3.65).Conclusion In the largest multicenter cohort of VBTLs to date, EVT demonstrated a substantial functional and survival benefit over medical management, establishing it as the preferred treatment strategy despite an increased risk of sICH. The anatomical complexity of tandem vertebrobasilar lesions should not preclude mechanical thrombectomy, particularly in patients presenting with severe neurological deficits.Disclosures M. Doheim: None. W. Li: None.