The aim of this study was to determine the long-term effects and determinants of success of cardiac pacing in patients affected by reflex syncope enrolled in the Syncope Unit Project 2 (SUP 2) study. Initial results have validated the effectiveness of a standardized guideline-based algorithm which can be used in clinical practice in order to select suitable candidates for cardiac pacing. In this prospective, multicentre, observational study, patients aged >40 years, affected by severe unpredictable recurrent reflex syncope, underwent carotid sinus massage (CSM), followed by tilt testing (TT) if CSM was negative, followed by implantation of an implantable loop recorder (ILR) if TT was negative. Those who had an asystolic response to one of these tests received a dual-chamber pacemaker. Of 281 patients who met the inclusion criteria, 137 (49%) received a pacemaker and were followed up for a mean of 26 ± 11 months: syncope recurred in 25 (18%) of them. At 3 years, the actuarial syncope recurrence rate was 20% 95% confidence interval (CI) 12-30 and was significantly lower than in 142 patients who did not receive a pacemaker and were observed by means of an ILR 43% (95% CI 29-57), P = 0.01. The 3-year recurrence rate was not different among 78 CSM+, 38 TT+, and 21 ILR+ patients, whereas it was lower in 20 patients with negative TT 5% (95% CI 0-15) than in 61 patients with positive TT 24% (95% CI 10-38). The benefit of cardiac pacing is maintained at 3 years, irrespective of the index diagnostic test, and is maximum in patients with negative TT. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01509534.