This study aimed to investigate the outcomes and effectiveness of different antithrombotic regimens at discharge in nonvalvular atrial fibrillation (NVAF) patients with acute ischemic stroke (AIS) and competing large artery atherosclerosis (LAA) mechanisms.In an observational study, we retrospectively analyzed the clinical and follow-up data of NVAF patients with AIS from January 2018 to December 2021 (NCT04080830). The subjects were grouped into 2 groups based on the presence or absence of competing LAA mechanisms. Stroke severity, short-term prognosis, and ischemic recurrence (a composite of ischemic stroke/TIA, myocardial infarction, or systemic embolism after index stroke), were compared between the 2 groups. Antithrombotic regimens at discharge were further categorized into antiplatelet and anticoagulant subgroups to analyze their effectiveness.Five hundred-one NVAF patients with AIS (129 with and 372 without competing LAA mechanisms) were included. Compared with the other group, the group with competing LAA mechanisms had a higher proportion of patients with a nondisabling mRS score (P <0.001), lower mortality rates at the 90-day follow-up ( P =0.048), and higher 180-day ischemic outcomes ( P =0.023). Subgroup analysis showed that the ischemic outcomes were not significantly different ( P =0.166) between the anticoagulant and antiplatelet subgroups in patients with competing LAA mechanisms. In contrast, it was numerically higher in the anticoagulant subgroup.NVAF patients with AIS due to competing LAA mechanisms had mild severity and a comfortable short-term prognosis; however, these patients had a higher risk of ischemic events. The optimal antithrombotic regimens in these patients remain unclear, and stroke mechanisms should be considered.Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.