Given the preventable morbidity and mortality associated with atrial fibrillation (AF), increased awareness of undiagnosed AF, and advances in mobile electrocardiogram (ECG) technology, there is a critical need to assess the effectiveness of using such technology to routinely screen for AF in clinical practice. VITAL-AF is a pragmatic trial that will test whether screening for AF using a single-lead handheld ECG in individuals 65 years or older during primary care visits will lead to an increased rate of AF detection. The study is a cluster-randomized trial, with 8 primary care practices randomized to AF screening and 8 primary care practices randomized to usual care. We anticipate studying approximately 16,000 patients in each arm. During the 1-year enrollment period, practice medical assistants will screen eligible patients who agree to participate during office visits using a single-lead ECG device. Automated screening results are documented in the electronic health record, and patients can discuss screening results with their provider during the scheduled visit. All single-lead ECGs are overread by a cardiologist. Screen-detected AF is managed at the discretion of the patient's physician. The primary study end point is incident AF during the screening period. Key secondary outcomes include new oral anticoagulation prescriptions, incident ischemic stroke, and major hemorrhage during a 24-month period following the study start. Outcomes are ascertained based on electronic health record documentation and are manually adjudicated. The results of this pragmatic trial may help identify a model for widespread adoption of AF screening as part of routine clinical practice.