BACKGROUND: Although cardiac resynchronization therapy (CRT) is beneficial in most heart failure patients, up to 40% do not respond to CRT. It has been suggested that multipoint left ventricle pacing (MPP) would increase the response rate. AIM: To assess the CRT response rate at 6 months in patients implanted with a CRT device with the MPP feature activated early after the implant. METHODS This was a multicentre, prospective, open-label and non-randomized study. The primary endpoint was response to biventricular pacing defined as >15% relative reduction in left ventricular end-systolic volume (LVESV) comparing echocardiography measurements performed at baseline and 6 months by a core laboratory. Among secondary endpoints the combined endpoint of mortality or all-cause hospitalizations was evaluated. Primary study endpoint and clinical outcomes were compared to a Quarto II control cohort. RESULTS: 105 patients were included. The response rate was 64.6% (97.5% lower confidence bound 53%). Mean relative reduction in LVESV was 25.3% and mean absolute increase in LVEF was 9.4%. The subjects with device programmed using anatomical approach had showed a trend toward higher responder rate than those using the electrical approach (72% vs. 61.1%, p= 0.32). Compared with Quarto II, the combined endpoint of mortality and or all-cause hospitalizations was lower in Quarto III (12.4% vs 25.4%, p=0.004). CONCLUSIONS: Early activation of MPP was not associated to an advantage increasing echocardiography responders to CRT at 6 months of follow up. Nevertheless, MPP was associated with better clinical outcomes in comparison to a historical control cohort. Patients programmed using widest pacing cathodes had a numerically higher responder rate.