Background and objective: The effect of endovascular therapy (EVT) in tandem lesion (TL) patients with baseline large core infarct is unclear. We investigated the safety and efficacy of EVT in TL patients with low ASPECTS (0-5). We also compared the safety of acute carotid stenting (CAS) in TLs with low ASPECTS. Methods: This prospective multicenter study from 16 centers included patients with anterior circulation TL from 2015-2020. Inclusion criteria were age ≥18 years, EVT for intracranial occlusion, and underwent treatment for extracranial ICA lesions with >70% stenosis. Patients were divided into ASPECTS 0-5 and 6-10 groups. Inverse Probability of Treatment Weighting (IPTW) was used to assess the association of outcomes. Results: Of the 691 patients, 44 had an ASPECTS 0-5 and 505 had ASPECTS 6-10. After matching, there were decreased odds of favorable shift in mRS at 90 days (30.7% vs 48%, OR: 0.52, CI:0.29-0.97; p=0.002), higher rates of sICH (11.4% vs 3.6%, OR: 3.18, CI: 1.07-9.49; p=0.038), 90-day mortality (35.9% vs 16.3%; OR: 2.35, CI: 1.16-4.74; p=0.017) and comparable rates of successful reperfusion (79.5% vs 88.7%; OR: 0.73, CI: 0.33-1.63, p=0.45), excellent reperfusion (50% vs 49.1%; OR: 1.35, CI: 0.72-2.53; p=0.35) excellent reperfusion (50% vs 49.1%; OR: 1.35, CI: 0.72-2.53; p=0.35) in the ASPECTS 0-5 compared with 6-10. Among patients with ASPECTS 0-5, no significant differences were noted for sICH (OR: 0.31, CI: 0.03-3.05; p=0.32), PH2 (OR: 1.14, CI: 0.26-5.02; p=0.86), petechial hemorrhages (OR: 0.79, CI: 0.10-6.05; p=0.82), and 90-day mortality (OR: 0.68, CI: 0.14-3.45; p=0.6) in patients with stenting (18/44) versus no-stenting (25/44). Conclusion: This multicenter cohort study of AIS patients with TLs demonstrated poor outcomes for functional independence at 90 days and higher rates of sICH and mortality in patients with low ASPECTS (0-5). Among patients with ASPECTS 0-5, rates of sICH and mortality were similar in stenting and non-stenting groups.