The antiarrhythmic effect of triple-site biventricular stimulation (Tri-V) is poorly understood. This study aims to evaluate the effect of cardiac resynchronization therapy (CRT) on ventricular arrhythmia (VA) with Tri-V using a single right ventricular (RV) and double left ventricular (LV) lead. Over a period of 3.5 years, 58 consecutive patients with New York Heart Association class IIIV heart failure, an LV ejection fraction of 0.35, and a QRS interval of 120 ms were enrolled. Acute haemodynamic responses to dual-site biventricular stimulation (Bi-V) and Tri-V were evaluated by assigning patients to a Bi-V or Tri-V group. Electrocardiogram parameters [QT interval, JT interval, and transmural dispersion of repolarization (TDR)] were measured over time after CRT. Spontaneous VA detected by telemetry was reviewed and confirmed. During a mean follow-up of 481 days after implantation, VA occurred in 2 of 22 patients in the Tri-V group and 14 of 36 patients in Bi-V group. Triple-site biventricular stimulation was thus associated with a decreased VA risk (P 0.044). Multivariate Cox analysis showed that Tri-V pacing prevented arrhythmic events as compared with Bi-V pacing (hazard ratio, 0.13; 95 confidence interval, 0.0290.610; P 0.009). Ventricular repolarization indices at 6 months were significantly shortened in Tri-V compared with Bi-V (QTc, 23.6 vs. 14.1, P 0.008; JTc, 21.4 vs. 7.7, P 0.005; TDRc, 39.9 vs. 17.0, P 0.001). Compared with Bi-V, Tri-V reduced VA during long-term follow-up. Improvements in repolarization parameters may result in antiarrhythmic effects.