Placement of left ventricular (LV) and right ventricular (RV) leads with maximal interlead separation is frequently sought during cardiac resynchronization therapy (CRT), but few published data are available to support this. This study examined the relation between LV and RV lead separation and the acute effects of CRT on cardiac contractility. A total of 51 consecutive patients who underwent CRT for standard indications with sufficient mitral regurgitation for echocardiographic assessment of contractility (using Doppler profiles of mitral regurgitation as a percentage of change in dP/dt [ΔdP/dt] with CRT on and off), successful transvenous LV lead placement, and postprocedural chest radiography were evaluated. The separation of the LV and RV lead tips (direct interlead distance and horizontal and vertical components) was determined on postprocedural posteroanterior and lateral radiographs. The corrected direct LV-RV interlead distance on the lateral radiograph was correlated with the ΔdP/dt (n = 51, r = 0.43, p = 0.002). The lateral interlead distance in the horizontal plane (r = 0.58, p <0.0001), but not the vertical plane (r = −0.28, p = NS), correlated with the ΔdP/dt. The corrected horizontal interlead distance on the lateral film was greater in acute hemodynamic responders to CRT (ΔdP/dt >25%) compared with nonresponders (14.4 ± 5.4 vs 9.2 ± 5.8 cm, p = 0.002). Other LV-RV measures on the posteroanterior and lateral radiographs did not correlate with the ΔdP/dt. Use of these findings may help to guide the sites of LV and RV lead placement to maximize the benefit derived from CRT.