Data from the completed "Suppression of Atrial Fibrillation by DDD+ Overdrive Pacing with Inos2 CLS (closed-loop system) Pacemakers" multicenter trial were retrospectively evaluated to examine the influence of concomitant antiarrhythmic drugs on the clinical success of conventional single site right atrial overdrive pacing compared with DDD pacing. The DDD+ overdrive algorithm provided > 90% atrial pacing at a rate slightly above the intrinsic atrial rate. Seventy-five patients with conventional pacing indications and paroxysmal, recurrent atrial tachyarrhythmia have completed the study. They were randomized to 6 months of DDD or DDD+ pacing, followed by mode crossover and an additional 6-month follow-up in the alternate mode. The incidence of atrial tachyarrhythmia during each period was compared using data on sustained (> 60 s) mode switch episodes stored in the pacemaker memory. A stable antiarrhythmic drug regimen was allowed during the study. beta-Adrenergic blockers and Class III antiarrhythmics, prescribed to 54.7% and 40.0% of patients respectively, were linked to minimal or no benefit of overdrive pacing compared with DDD pacing. In contrast, patients untreated with beta-adrenergic blockers or Class III drugs had a significant reduction in atrial tachyarrhythmia burden of > 5 hours/patient per week (P < 0.05) during overdrive. Changes with Class I and Class IV antiarrhythmic drugs, prescribed to 18.7% and 13.3% of patients, respectively, were insignificant. Our data indicate that clinical trials that prohibit the use of beta-adrenergic blockers may record more favorable outcomes with dynamic atrial overdrive algorithms versus conventional DDDR pacing, than studies allowing concomitant beta-adrenergic blockade.