Background: Surgical left atrial appendage (LAA) closure concomitant to open-heart surgery prevents thromboembolism in high-risk patients. Nevertheless, high-level evidence does not exist for LAA closure performed in patients with any CHA₂DS₂-VASc score and preoperative atrial fibrillation or flutter (AF) status—the current trial attempts to provide such evidence. Methods: The study is designed as a randomized, open-label, blinded outcome assessor, multicenter trial of adult patients undergoing first-time elective open-heart surgery. Patients with and without AF and any CHA₂DS₂-VASc score will be enrolled. The primary exclusion criteria are planned LAA closure, planned AF ablation, or ongoing endocarditis. Before randomization, a three-step stratification process will sort patients by site, surgery type, and preoperative or expected oral anticoagulation treatment. Patients will undergo balanced randomization (1:1) to LAA closure on top of the planned cardiac surgery or standard care. Block sizes vary from 8 to 16. Neurologists blinded to randomization will adjudicate the primary outcome of stroke, including transient ischemic attack (TIA). The secondary outcomes include a composite outcome of stroke, including TIA, and silent cerebral infarcts, an outcome of ischemic stroke, including TIA, and a composite outcome of stroke and all-cause mortality. LAA closure is expected to provide a 60% relative risk reduction. In total, 1500 patients will be randomized and followed for 2 years. Discussion: The trial is expected to help form future guidelines within surgical LAA closure. This statistical analysis plan ensures transparency of analyses and limits potential reporting biases. Trial registration: Clinicaltrials.gov, NCT03724318. Registered 26 October 2018, https://clinicaltrials.gov/study/NCT03724318. Protocol version: https://doi.org/10.1016/j.ahj.2023.06.003.