Background Atrial fibrillation (AF), with a prevalence of 1% to 2%, is the most common cardiac arrhythmia. Without antithrombotic treatment, the annual risk of a cardioembolic event is 5% to 6%. The source of a cardioembolic event is a thrombus, which is usually formed in the left atrial appendage (LAA). Prevention of cardioembolic events involves treatment with anticoagulant drugs: either vitamin K antagonists or, recently, novel oral anticoagulants (NOAC). The other (nonpharmacologic) option for the prevention of a cardioembolic event involves interventional occlusion of the LAA. Objective To determine whether percutaneous LAA occlusion is noninferior to treatment with NOAC in AF patients indicated for long-term systemic anticoagulation. Study design The trial will be a prospective, multicenter, randomized noninferiority trial comparing 2 treatment strategies in moderate to high-risk AF patients (ie, patients with history of significant bleeding, or history of cardiovascular event(s), or a with CHA(2)DS(2)VASc >= 3 and HAS-BLED score >= 2). Patients will be randomized into a percutaneous LAA occlusion (group A) or a NOAC treatment (group B) in a 1: 1 ratio; the randomization was done using Web-based randomization software. A total of 396 study participants (198 patients in each group) will be enrolled in the study. The primary end point will be the occurrence of any of the following events within 24 months after randomization: stroke or transient ischemic attack (any type), systemic cardioembolic event, clinically significant bleeding, cardiovascular death, or a significant periprocedural or device-related complications. Conclusion The PRAGUE-17 trial will determine if LAA occlusion is noninferior to treatment with NOAC in moderate-to high-risk AF patients.