Objectives: This study aimed to compare multipoint pacing (MPP) to optimal biventricular pacing with a quadripolar left ventricular (LV) lead and find factors associated with hemodynamic response to MPP. Background: MPP with a quadripolar LV lead may increase response to cardiac resynchronization therapy. Methods: Heart failure patients with a left bundle branch block underwent cardiac resynchronization therapy implantation. Q to LV sensing interval divided by the intrinsic QRS duration was measured. Invasive pressure-volume loops were assessed during 4 biventricular pacing settings and 3 MPP settings, using 4 atrioventricular delays. Hemodynamic response was defined as change in stroke work (Δ%SW) compared with baseline measurements during intrinsic conduction. Δ%SW of MPP was compared with conventional biventricular pacing using the distal electrode and the electrode with highest Δ%SW (BIV-OPT). Results: Forty-three patients were analyzed (age 66 ± 10 years, 63% men, 30% ischemic cardiomyopathy, LV ejection fraction 29 ± 8%, and QRS duration 175 ± 13 ms). Q to local LV sensing interval corrected for QRS duration was 84 ± 8%, and variation between LV electrodes was 9 ± 5%. Compared with conventional biventricular pacing using the distal electrode, MPP showed a significant higher increase of SW (Δ%SW +15 ± 35%; p < 0.05) with a large interindividual variation. There was no significant difference in Δ%SW with MPP compared with BIV-OPT (−5 ± 24%; p = 0.19). Male sex and low LV ejection fraction were associated with increase in Δ%SW due to MPP versus BIV-OPT in multivariate analysis, while ischemic cardiomyopathy was only associated in univariate analysis. Conclusions: Optimization of the pacing site of a quadripolar LV lead is more important than to program MPP. However, specific subgroups (i.e., especially men) may benefit substantially from MPP.