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A significant proportion of patients implanted with biventricular (BiV) devices fail to respond. Clinical response may be improved by additional ventricular stimulation sites. This single-centre, double-blinded randomized crossover trial aimed to determine whether long-term multisite ventricular pacing is superior to conventional BiV pacing in heart failure patients.A total of 43 patients referred for cardiac resynchronization therapy (CRT) underwent transvenous implantation of a triventricular (TriV) device. Pacing leads were positioned in the right ventricular (RV) apex and a lateral coronary sinus (CS) branch, with a third ventricular lead implanted in a further lateral CS branch in 23 patients (group A) and on the high RV septum in 20 patients (group B). Devices were programmed in a randomized order to four pre-determined pacing configurations: conventional BiV, TriV, and dual-site and single-site left bentricular (LV) or RV pacing for 3-month periods with clinical and echo assessment at the end of each period. The primary endpoint was the comparison of 6 min walk distance (6MW) after 3 months of BiV vs. TriV pacing; secondary endpoints were Minnesota Living With Heart Failure (MLWHF) scores, and LV dimensions and function. The 12-month follow-up period was completed by 37 patients. Compared with BiV pacing, TriV pacing resulted in significant improvements in 6MW (451 ± 112 m vs. 425 ± 119 m, P = 0.008), MLWHF (32 ± 19 vs. 38 ± 24, P = 0.036), LV end-systolic volume (158 ± 79mL vs. 168 ± 76 mL, P < 0.05), and ejection fraction (30 ± 8% vs. 27 ± 8%, P < 0.05).TriV pacing was associated with significant improvements in clinical and echocardiographic parameters compared with BiV pacing.