Closed-loop stimulation (CLS) is a physiological system for adaptive rate pacing based on monitoring and processing of the intracardiac impedance. The "standard" CLS algorithm (SCLS) requires continuous ventricular pacing. A new, enhanced CLS algorithm (ECLS) provides rate modulation during sensed and paced ventricular depolarizations. The aim of this study was to validate ECLS and to compare its effectiveness with that of SCLS. Ten patients received Inos2+ CLS pulse generators. SCLS and ECLS were uploaded to the device and evaluated in a randomized, crossover fashion at 30 and 45 days after pacemaker implantation. At each follow-up visit, ambulatory and posture tests were performed. Heart rate (HR) during daily activity was evaluated based on 24-hour Holter recordings. During all phases of the ambulatory test, both algorithms provided physiologically appropriate rates in all patients. The proportion of sensed ventricular events was significantly higher in ECLS (93.9%) than in SCLS (0.7%). The proportion of paced ventricular events during 24 hours was substantially lower with ECLS (25.7%) than with SCLS (98.4%). Postural changes did not influence HR with either algorithm. The Holter recordings indicated prompt, safe, and effective rate modulation appropriate to patients activity. In conclusion, analysis of these clinical data demonstrated the safety and effectiveness of the ECLS algorithm. Moreover, with this algorithm the ventricle is paced only when required, which may be expected to retard battery depletion and retain the natural ventricular activation pattern whenever possible.