Vectorcardiographic QRS area (QRSarea) predicts clinical outcomes after cardiac resynchronization therapy (CRT). Myocardial scar adversely affects clinical outcomes after CRT. The purpose of this study in patients with an ideally deployed quadripolar left ventricular (LV) lead (QUAD) was to determine whether reducing QRSarea leads to an acute hemodynamic response (AHR) and whether scar affects this interaction. Patients (n = 26; age 69.2 ± 9.12 years [mean ± SD]) underwent assessment of the maximum rate of change of LV pressure (ΔLV dP/dtmax) during CRT using various left ventricular pacing locations (LVPLs). Cardiac magnetic resonance (CMR) scan was used to localize LV myocardial scar. Interindividually, ΔQRSarea (area under the receiver operating characteristic curve [AUC] 0.81; P <.001) and change in QRS duration (ΔQRSd) (AUC 0.76; P <.001) predicted ΔLV dP/dtmax after CRT. Scar burden correlated with ΔQRSarea (r = 0.35; P = .003), ΔQRSarea (r = 0.35; P = .003), and ΔQRSd (r = 0.46; P <.001). A reduction in QRSarea was observed with LVPLs remote from scar (-3.28 ± 38.1 μVs) or in LVPLs in patients with no scar at all (-43.8 ± 36.8 μVs), whereas LVPLs over scar increased QRSarea (22.2 ± 58.4 μVs) (P <.001 for all comparisons). LVPLs within 1 scarred LV segment were associated with lower ΔLV dP/dtmax (-2.21% ± 11.5%) than LVPLs remote from scar (5.23% ±10.3%; P <.001) or LVPLs in patients with no scar at all (10.2% ± 7.75%) (both P <.001). Reducing QRSarea improves the AHR to CRT. Myocardial scar adversely affects ΔQRSarea and the AHR. These findings may support the use of ΔQRSarea and CMR in optimizing CRT using QUAD.