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Background: We aimed to describe the safety and efficacy of mechanical thrombectomy (MT) with or without intravenous thrombolysis (IVT) for patients with tandem lesions and whether using intraprocedural antiplatelet therapy influences MT's safety with IVT treatment., Methods: This is a subanalysis of a pooled, multicenter cohort of patients with acute anterior circulation tandem lesions treated with MT from 16 stroke centers between January 2015 and December 2020. Primary outcomes included symptomatic intracranial hemorrhage (sICH) and parenchymal hematoma type 2. Additional outcomes included hemorrhagic transformation, successful reperfusion (modified Thrombolysis in Cerebral Infarction score 2b-3), complete reperfusion (modified Thrombolysis in Cerebral Infarction score 3), favorable functional outcome (90-day modified Rankin Scale score 0-2), excellent functional outcome (90-day modified Rankin Scale score 0-1), in-hospital mortality, and 90-day mortality., Results: Of 691 patients, 512 were included (218 underwent IVT+MT and 294 MT alone). There was no difference in the risk of sICH (adjusted odds ratio [aOR], 1.22 [95% CI, 0.60-2.51]; P =0.583), parenchymal hematoma type 2 (aOR, 0.99 [95% CI, 0.47-2.08]; P =0.985), and hemorrhagic transformation (aOR, 0.95 [95% CI, 0.62-1.46]; P =0.817) between the IVT+MT and MT alone groups after adjusting for confounders. Administration of IVT was associated with an increased risk of sICH in patients who received intravenous antiplatelet therapy (aOR, 3.04 [95% CI, 0.99-9.37]; P =0.05). The IVT+MT group had higher odds of a 90-day modified Rankin Scale score 0 to 2 (aOR, 1.72 [95% CI, 1.01-2.91]; P =0.04). The odds of successful reperfusion, complete reperfusion, 90-day modified Rankin Scale score 0 to 1, in-hospital mortality, or 90-day mortality did not differ between the IVT+MT versus MT alone groups., Conclusions: Our study showed that the combination of IVT with MT for tandem lesions did not increase the overall risk of sICH, parenchymal hematoma type 2, or overall hemorrhagic transformation independently of the cervical revascularization technique used. However, intraprocedural intravenous antiplatelet therapy during acute stent implantation might be associated with an increased risk of sICH in patients who received IVT before MT. Importantly, IVT+MT treatment was associated with a higher rate of favorable functional outcomes at 90 days., Competing Interests: Disclosures A.E. Hassan is a consultant/speaker at Medtronic, Microvention, Stryker, Penumbra, Cerenovus, Genentech, GE Healthcare, Scientia, Balt, vizai, Insera therapeutics, Proximie, NeuroVasc, NovaSignal, Vesalio, Rapid Medical, Imperative Care and Galaxy Therapeutics; principal investigator for COMPLETE study—Penumbra, LVO SYNCHRONISE—vizai, Millipede Stroke Trial—Perfuze, RESCUE—ICAD, Medtronic; steering committee/publication committee member for SELECT, DAWN, SELECT 2, EXPEDITE II, EMBOLISE, CLEAR, ENVI, DELPHI, DISTALS. Dr Divani performed fundings at the University of New Mexico Center for Brain Recovery and Repair Center of Biomedical Research Excellence through Grant Number (NIH P20GM109089, Pilot PI), W81XWH-17-2-0053 (PI), 1R21NS130423-01 (PI). Dr Ribo is consultant at aptaTargets, Anaconda Biomed, Philips, Medtronic, Cerenovus, Vesalio, and Rapid Pulse outside the submitted work. Dr Abraham is a consultant at Penumbra Inc, Qapel, Stryker Corporation. Dr Fifi is a consultant at Cerenovus, Stryker Corporation, Microvention Inc; received stock from Cerebrotech, Imperative Care, Sime&Cure; and received grants from viz AI. Data and Safety Monitoring: MIVI. Dr Yoo is a consultant for Johnson & Johnson Medical Devices & Diagnostics Group—Latin America, LLC, Nicolab, Penumbra Inc, Philips, Vesalio, ZOLL Circulation Inc; received grants from Genetech, USA Inc, Johnson & Johnson Medical Devices & Diagnostics Group—Latin America, LLC, Medtronic, Penumbra Inc, Stryker; Employment at HCA Healthcare; received stock from Insera, Nicolab; performed data and safety monitoring at National Institutes of Health. Dr Mokin is a consultant at Johnson & Johnson Medical Devices & Diagnostics Group—Latin America, LLC, Medtronic, MicroVention Inc, received stock from Bendit Technology, BrainQ, Serenity medical, Synchrone. Dr Yavagal is a consultant at Athersys, Gravity Medical Technology, Johnson & Johnson Health Care Systems Inc, Medtronic USA Inc, Poseydon, Stryker Corporation, Vascular Dynamics; received stock from Athersys, Poseydon, Rapid Medical. Dr Jovin is a consultant at Contego Medical Inc received stock from Anaconda, Freeox Biotech, Galaxy, Kandu, Methinks, Route92, vizai. Grant: Medtronicm, USA, Inc, Stryker Corporation; performed data and safety monitoring at Johnson & Johnson, Cerenovus. Dr Sheth is a consultant at vizAI, Penumbra, Imperative Care; received grants from NIH, vizAI; and took ownership for Motif Neuroscience (not related to this article). Dr Ortega-Gutierrez received grants from NIH-NINDS (R01NS127114-01, R03NS126804), Stryker, Medtronics, Microvention, Penumbra, IschemiaView, vizai, and Siemens; he is a consultant at Medtronic and Stryker Neurovascular. The other authors report no conflicts.