Objective To compare the outcomes of patients with anterior circulation large artery atherosclerosis (LAA) stroke with or without ipsilateral internal carotid artery occlusion after endovascular treatment. Methods The subgroups of a multicenter randomized clinical trial DIRECT-MT were retrospectively analyzed. The baseline characteristics and prognoses of patients with LAA stroke with isolated intracranial artery occlusion (intracranial occlusion group) and LAA stroke with tandem occlusion (tandem occlusion group) with ipsilateral extracranial internal carotid artery occlusion were compared, and the effects of different mechanism characteristics (atherosclerosis or arterial embolism) on clinical outcomes were analyzed. Results There were 108 patients with LAA stroke, including 63 cases in the tandem occlusion group and 45 cases in the intracranial occlusion group. The proportion of patients with hypertension history in the intracranial occlusion group was higher than that in the tandem occlusion group (77.8%[35/45] vs 52.4%[33/63], P=0.007). The most common site of intracranial occlusion in the intracranial occlusion group was the middle cerebral artery M1 segment (88.6%, 39/44), while those in the tandem occlusion group were the internal carotid artery intracranial segment (49.2%, 31/63) and the middle cerebral artery M1 segment (49.2%, 31/63) (P<0.001). There were no significant differences in age, gender, preoperative use of antithrombotic drugs or statins, history of stroke, atrial fibrillation or smoking, baseline modified Rankin scale (mRS) or National Institutes of Health stroke scale (NIHSS) score, whether receiving intravenous thrombolysis or not, collateral circulation, or treatment process time between the 2 groups (all P>0.05). There was no significant difference in the proportions of patients with 90-d mRS score of 0-2 between the 2 groups (53.3%[24/45] vs 41.9%[26/62], P=0.243). The successful reperfusion rate in the intracranial occlusion group was higher than that in the tandem occlusion group (93.3%[42/45] vs 77.4%[48/62], P=0.026), but the proportion of vascular recanalization within 24-72 h after surgery was lower than that in the tandem occlusion group (57.1%[24/42] vs 77.2%[44/57], P=0.034), and the final infarct volume was smaller than that in the tandem occlusion group (20.1[0.3, 65.3] mL vs 34.5[19.9, 124.6] mL, P=0.025). There were no significant differences in other secondary outcomes such as postoperative NIHSS score, 90-d EuroQoL Group 5-dimension 5-level self-report questionnaire on health-related quality of life (EQ-5D-5L) score or Barthel index between the 2 groups (all P>0.05). The mortality within 90 d, the incidence of asymptomatic and symptomatic intracranial hemorrhage, the incidence of cerebral infarction in other vascular regions at 5-7 d, and the incidence of embolization in a new territory were similar between the 2 groups, with no significant differences (all P>0.05). Conclusion Compared with isolated intracranial occlusion, tandem occlusion caused by atherosclerosis has a lower successful reperfusion rate on the last angiography and a larger infarct volume, but the vascular recanalization rate is higher at 24-72 h after surgery, and the good prognosis rate of neurological function and the incidence of adverse events are similar to those of intracranial occlusion.