Background More than 200,000 permanent pacemakers will be implanted in the United States in 2000 at a cost of more than $2 billion. Sick sinus syndrome (SSS) will likely account for approximately half of all cases necessitating implantation. Pacemaker technology permits the selection of ventricular (single-chamber) or dual-chamber devices. However, clinical and outcomes data are inadequate to support a clear recommendation that one or the other type of device be used. Methods The Mode Selection Trial (MOST) is a single-blind study supported by the National Heart, Lung, and Blood Institute designed to enroll 2000 patients with SSS. All patients will receive a DDDR pacemaker programmed to VVIR or DDDR before implantation. The average time of follow-up will be 3 years. MOST has a >90% power to detect a 25% reduction in the primary end point—nonfatal stroke or total (all cause) mortality—in the DDDR-treated group. Secondary end points will include health-related quality of life and cost effectiveness, atrial fibrillation, and development of pacemaker syndrome. Prespecified subgroups for analysis will include women and the elderly. Enrollment was completed in October 1999, with a total of 2010 patients. Results The median age of the first 1000 enrolled patients is 74 years, with 25% of patients 80 years or older. Women comprise 49%, and 17% are nonwhite, predominantly black (13%). Before pacemaker implantation, 22% of patients reported a history of congestive heart failure, 11% coronary angioplasty, and 25% coronary bypass surgery. Supraventricular tachycardia including atrial fibrillation was present in 53% of patients. A prior stroke was reported by 12%. Antiarrhythmic therapy was in use in 18% of patients. Conclusions MOST will fill the clinical need for carefully designed prospective studies to define the benefits of dual-chamber versus single-chamber ventricular pacing in patients with SSS. The MOST population is typical of the overall pacemaker population in the United States. Thus the final results of MOST should be clinically generalizable. (Am Heart J 2000; 140:541-51.)