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Background: In patients with acute ischemic strokes (AIS) and milder symptoms (NIHSS=5) harboring a large vessel occlusion (LVO) best clinical management is unclear. To describe the safety and efficacy of immediate mechanical thrombectomy (MT) in patients with LVO and milder symptoms versus best medical management, including rescue MT.Methods: Retrospective cohort study on consecutive patients for a descriptive analysis regarding clinical and safety outcomes. From local prospectively run databases of six international comprehensive stroke centers data was pooled. 300 Patients with LVO (distal internal carotid artery, MCA-M1 and/or M2 segments, or basilar artery with or without tandem occlusions) and milder symptoms were identified and divided into two groups for analysis: immediate MT (i-MT) or best medical management which included rescue MT after neurological deterioration (n/r-MT). Uni- and multivariate analysis were performed to compare baseline and outcome variables across the two groups. Additional comparisons were performed after patient-level matching for age, baseline NIHSS and occlusion site. The primary outcome was defined as good outcome (modified rankin scale [mRS] 0-2) at day 90. Secondary outcomes were, among others, modified shift analyses at day 90. Safety outcome was symptomatic intracranial hemorrhage (sICH) as defined by the European Cooperative Acute Stroke Study (ECASS) II and mortality at day 90.Results: Compared to n/r-MT (n=220), patients with i-MT (n=80) were younger (65.3+/-13.5 vs. 69.5+/-14.1, p=0.021), had more often atrial fibrillation (44.8% vs. 28.2%, p=0.012), higher baseline NIHSS (4, 0-5 vs. 3, 0-5, p=0.005), more MCA-M1 (41.3% vs. 21.9%) and less MCA-M2 (28.8% vs. 49.3%, p=0.016) occlusions. The adjusted odds ratio for good outcome was 3.1 95% CI: 1.4-6.9 favoring i-MT. In the matched analysis, there was a 14.4% absolute difference in good outcome (84.4% vs. 70.1%, p=0.03) and a significant modified mRS shift (OR 2.29, 95% CI: 1.05-4.98) at day 90 favoring i-MT. There were no safety concerns.Conclusions and Relevance: The observed benefit-safety profile favors immediate MT in patients with milder symptoms and LVO.