Abstract Body: Background: Medium vessel occlusion (MeVO) accounts for approximately one-third of all acute ischemic strokes and presents distinct management challenges, despite being less severe than large vessel occlusion (LVO). While endovascular treatment (EVT) has proven superior to best medical treatment (BMT) in LVO, its efficacy and safety in MeVO are not yet fully established. The recently published DUSK trial, which did not demonstrate significant benefits of EVT for MeVO, has not been included in prior reviews, making it essential to integrate and critically evaluate the implications of this new evidence. Aim: This meta-analysis aims to evaluate the efficacy and safety of EVT compared to BMT in patients with MeVO. Methods: We conducted a systematic search of PubMed, Embase, and the Cochrane Library up to August 2024, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our analysis focused exclusively on peer-reviewed randomized controlled trials (RCTs) that compared the efficacy of EVT with BMT in patients with MeVOs. The primary outcomes were excellent functional outcome (defined as modified Rankin Scale [mRS] 0-1) and functional independence (defined as mRS 0-2) at 3 months. Effect sizes were computed as odd ratio (OR) with random-effect models. Results: Three RCTs with 862 patients (448 randomized into EVT vs. 414 randomized into BMT) were included. The pooled analysis demonstrated that EVT did not significantly increase the likelihood of achieving an excellent functional outcome (mRS 0-1: OR 0.89, 95% CI 0.67–1.18, p = 0.42) or functional independence (mRS 0-2: OR 0.93, 95% CI 0.62–1.40, p = 0.73) at 3 months compared to BMT. Additionally, EVT did not significantly elevate the risk of symptomatic intracranial hemorrhage (sICH: OR 1.13, 95% CI 0.55–2.33, p = 0.75) or mortality (mRS 6: OR 1.19, 95% CI 0.53–2.65, p = 0.67). Conclusions: Our systematic review and meta-analysis suggest that EVT for MeVO is not associated with a significant improvement in functional outcomes or an increased risk of adverse events such as sICH and mortality at 3 months, when compared to BMT. These findings underscore the need for further investigation, particularly with forthcoming RCTs to clarify the role of EVT in this patient population.