AIMS: Cardiac resynchronization therapy (CRT) via biventricular pacing (BIVP) is an effective treatment, but non-responders are at a higher risk of death and heart failure (HF) hospitalizations compared with CRT responders. The MORE-CRT MPP trial aimed to evaluate whether CRT with multipoint pacing (MPP) is associated with improved clinical outcomes in CRT non-responders. METHODS AND RESULTS: Cardiac resynchronization therapy patients were treated with conventional BIVP for 6 months and then assessed for CRT response (left ventricular end-systolic volume relative reduction >15% vs. baseline). Cardiac resynchronization therapy non-responders were 1:1 randomized to BIVP or MPP and followed for 6 months. The main endpoint of this secondary analysis was HF hospitalizations or all-cause mortality. Of 3724 CRT patients (67 ± 11 years, 1050 female), 1677 were non-responders and randomized to MPP or BIVP, of whom 1421 (722 MPP and 699 BIVP) had complete data. In a mean follow-up of 5 ± 1 months after randomization, MPP was associated with a lower incidence of HF hospitalizations or all-cause mortality [48/722 (6.64%)] compared with BIVP (73/699 (10.44%), RRR = 36% (95% CI=±4%), P = 0.0107). At multivariable analysis, MPP was associated with a lower occurrence of the main endpoint (odds ratio = 0.60, P = 0.0124). At logistic regression analysis, HF hospitalizations or all-cause death were lower with MPP vs. BIVP in the whole population and in many patients subgroups, e.g. ischaemic patients and patients with long (>105 ms) interventricular electrical delay. CONCLUSION: In the MORE-CRT MPP randomized trial, MPP was associated with a significant reduction of all-cause mortality and HF hospitalizations in prior non-responders to conventional biventricular pacing.