Abstract Background Cardiac resynchronization therapy (CRT) reduces cardiac electrical dyssyncrhony and improves clinical outcomes in selected symptomatic patients with left ventricular (LV) systolic dysfunction. However, patients after conventional CRT (Bi-V) have residual cardiac electrical dyssynchrony. CRT with multi-site pacing has gained attention to improve short-term outcome refractory to BiV. However, long-term follow up outcome is still uncertain. We evaluated the efficacy of CRT with triple-site ventricular stimulation (Tri-V), involving 2 LV lead in 2 anatomically separated veins and a single RV lead in RV apex for long-term follow up period. Methods Ninety-two consecutive patients with New York Heart Association class II-IV heart failure, LV ejection fraction <0.35, and QRS interval >120ms, who underwent CRT implantation between 2010 and 2016, were enrolled. Acute hemodynamic responses to temporary dual-site and triple-site ventricular pacing were evaluated, and patients were assigned to either the Bi-V or Tri-V group based on the results. The primary endpoint was the HF clinical composite score, which scores patients as improved, unchanged, or worsened. The secondary endpoint included cumulative survival from any cause of death and HF hospitalization. Results Tri-V was successfully implanted in 32 patients. Five patients were excluded during follow-up because of uncaptured pacing in one of the LV leads. One year post-implantation, the clinical composite score significantly improved in 84% of Tri-V patients compared to 57% in the Bi-V group (p=0.026). After a median follow-up of 12.0 years, there was no significant difference about all-cause mortality between Tri-V and Bi-V (p=0.147). However, Tri-V group showed significant lower HF hospitalization (p=0.005) than Bi-V group. The number of battery exchange was not significantly different between Tri-V than Bi-V group (1.4±0.7 vs. 1.2±0.8, p=0.361). Conclusion CRT with Tri-V, characterized by stable lead parameters, appears to offer greater long-term benefits than Bi-V in terms of clinical status without excessive battery exchanges.figure