Recent trials confirmed the efficacy and safety of endovascular thrombectomy in patients with low Alberta Stroke Program Early Computed Tomography Score (ASPECTS); however, evidence in tandem lesions is limited. This study evaluates endovascular thrombectomy safety and efficacy in patients with acute large-vessel occlusion with tandem lesions, stratified by baseline ASPECTS. We conducted a retrospective analysis of data from 16 centers. Inclusion criteria included the following: age ≥18 years, anterior circulation tandem lesions, endovascular thrombectomy <24 hours of symptom onset, and ≥70% internal carotid artery stenosis/occlusion. Patients were categorized into low (0-5) and high (6-10) ASPECTS. Inverse probability of treatment weighting matching was used to balance the groups. Primary outcomes included the following: 90-day modified Rankin Scale (mRS) score 0 to 2 and symptomatic intracranial hemorrhage. Secondary outcomes included the following: ordinal mRS, mRS 0 to 3, modified Thrombolysis in Cerebral Infarction ≥2b and 2c-3, petechial hemorrhage, parenchymal hematoma (1/2), early neurologic improvement, and mortality. Of 691 patients, 44 had ASPECTS 0 to 5 and 505 had ASPECTS 6 to 10. Patients with low ASPECTS had lower odds of 90-day mRS 0 to 2 (adjusted odds ratio [OR], 0.48; P=0.036) and higher odds of symptomatic intracranial hemorrhage (adjusted OR, 3.78; P=0.014). Additional significant differences were found in mRS shift, mRS 0 to 3, parenchymal hematoma 2, and mortality. In interaction analysis, the association between low ASPECTS and functional outcome persisted only in the internal carotid artery occlusion subgroup, with no significant interaction indicating no reason to suppose a difference between the effect of both subgroups. Endovascular thrombectomy in patients with tandem lesions with low ASPECTS is associated with reduced odds of functional recovery and increased symptomatic intracranial hemorrhage risk, when compared with patients with high ASPECTS. However, 30% of patients with low ASPECTS achieved 90-day functional independence, suggesting potential benefit for a nonnegligible proportion of patients.