Current recommendations regarding the use of surgical left atrial appendage (LAA) closure to prevent thromboembolisms lack high-level evidence. Patients undergoing open-heart surgery often have several cardiovascular risk factors and a high occurrence of postoperative atrial fibrillation (AF) – with a high recurrence rate – and are thus at a high risk of stroke. Therefore, we hypothesized that concomitant LAA closure during open-heart surgery will reduce mid-term risk of stroke independently of preoperative AF status and CHADS-VASc score. This protocol describes a randomized multicenter trial. Consecutive participants ≥18 years scheduled for first-time planned open-heart surgery from cardiac surgery centers in Denmark, Spain, and Sweden are included. Both patients with a previous diagnosis of paroxysmal or chronic AF, as well as those without AF, are eligible to participate, irrespective of their CHADS-VASc score. Patients already planned for ablation or LAA closure during surgery, with current endocarditis, or where follow-up is not possible are considered non-eligible. Patients are stratified by site, surgery type, and preoperative or planned oral anticoagulation treatment. Subsequently, patients are randomized 1:1 to either concomitant LAA closure or standard care (i.e., open LAA). The primary outcome is stroke, including transient ischemic attack, as assigned by two independent neurologists blinded to the treatment allocation. To recognize a 60% relative risk reduction of the primary outcome with LAA closure, 1500 patients are randomized and followed for two years (significance level of 0.05 and power of 90%). The LAACS-2 trial is likely to impact the LAA closure approach in most patients undergoing open-heart surgery.Copyright © 2023. Published by Elsevier Inc.