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Objectives This study sought to compare the Intrinsic Rhythm Support (IRSplus) and Ventricular Pace Suppress (VpS) in terms of right ventricular pacing percentage (VP %), mean atrioventricular interval (MAVI), atrial fibrillation, and cardiac volumes. Background Modern pacemakers are provided with algorithms for reducing unnecessary ventricular pacing. These may be classified as: periodic search for intrinsic atrioventricular (AV) conduction prolonging the AV delay accordingly; or DDD-ADI mode switch. The IRSplus and VpS algorithms belong to the former and latter classes, respectively. Methods Patients with sick sinus dysfunction without evidence of II/III degree AV block were 1:1 randomized to 6-month periods of either IRSplus or VpS, and then crossed over. Subsequent follow-ups were at the 12th month after randomization for device data retrieving, and at the 18th month with the same device programming for echocardiographic assessment. Results A total of 230 patients (62% males, median age 75 years [interquartile range: 69 to 79 years]) were enrolled. At a linear mixed-model analysis with order of treatment and investigational sites as nested random effects, differences in VP% and MAVI reached statistical significance: VP% was 1% (0% to 11%) during IRSplus and 3% (0% to 26%) during VpS (p = 0.029); MAVI was 225 ms (198 to 253 ms) during IRSplus and 214 ms (188 to 240 ms) during VpS (p = 0.014). No differences were observed in atrial fibrillation burden and incidence, ejection fraction, and cardiac volumes. Conclusions Both IRSplus and VpS algorithms ensured VP% ≤3% in most patients with sinus node dysfunction and preserved AV conduction. The IRSplus was slightly more efficient in reducing VP% at the expense of a small MAVI increase, with statistical but clinically insignificant differences. (Ventricular Pace Suppression Versus Intrinsic Rhythm Support Study; NCT01528657 )