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Although current guidelines advocate pretreatment with intravenous thrombolysis (IVT) in all eligible patients with acute ischemic stroke with large-vessel occlusion before mechanical thrombectomy, there are observational data questioning the efficacy of this approach. One of the main arguments in favor of IVT pretreatment is the potential for tissue-type plasminogen activator–induced successful reperfusion (SR) before the onset of endovascular procedure.We performed a systematic review and meta-analysis of randomized controlled clinical trials and observational cohorts providing rates of SR with IVT in patients with large-vessel occlusion before the initiation of mechanical thrombectomy. We also performed subgroup analyses according to study type (randomized controlled clinical trials versus observational) and according to the inclusion per protocol of patients with tandem (intracranial/extracranial) occlusions.We identified 13 eligible studies (7 randomized controlled clinical trials and 6 observational cohorts), including 1561 patients with acute ischemic stroke (median National Institutes of Health Stroke Scale score, 17) with large-vessel occlusion. SR following IVT and before mechanical thrombectomy was documented in 11% (95% confidence interval, 7%–16%), with no difference among cohorts derived from randomized controlled clinical trials and observational studies. There was significant heterogeneity across included studies both in the overall analysis and among subgroups (I2>84%; P for Cochran Q, <0.001). Higher tissue-type plasminogen activator–induced SR rates were documented in studies reporting the exclusion of tandem occlusions (17%; 95% confidence interval, 11%–23%) compared with the rest (7%; 95% confidence interval, 4%–11%; P for subgroup differences, 0.003).Pretreatment with systemic thrombolysis in patients with large-vessel occlusion eligible for mechanical thrombectomy results in SR in 1 of 10 cases, negating the need for additional endovascular reperfusion. Tandem occlusions seem to be the least responsive to IVT pretreatment.