Cardiac resynchronization therapy (CRT) is an effective treatment for patients with advanced heart failure. Nearly 30% of candidates are inadequate responders. Proper patient selection, left ventricle (LV) lead placement optimization, and optimization of the programming of the CRT device are important approaches to improve outcome of CRT. We examined the role of three-dimensional (3D) echocardiography in determining the optimal LV lead position as a method of optimizing CRT response. Forty-seven patients with a mean age of 60.2 ± 11.1years including five (10.6%) females, all having advanced CHF (EF <35%, LBBB >120mesc, or non-LBBB >150msec, with NYHA II-III or ambulatory class IV) were enrolled. Detailed history (NYHA class, Minnesota living with heart failure questionnaire), clinical examination, 6-min walk test, and standard 2D echocardiography were done in all cases. 3D echo detailed analysis of the LV 16 segments was done to determine the latest wall to reach the minimal systolic volume. Multisite pacing was done blind to the 3D echo data achieving a stable LV lead position in mid LV segment. This exact fluoroscopic site was determined (in two orthogonal views) and correlated with 3D most delayed area using a resized 16-segment schema. Patients were classified retrospectively into group A with concordance between the delayed LV area and LV lead position and group B with discordance between both. Patients were followed up after 3-6 (5.1 ± 1.8) months. Patients with reduction of 2D LV end-systolic volume of ≥10% at follow-up were termed volumetric responders. Poorly echogenic patients and those with decompensated NYHA class IV, sustained atrial arrhythmias, and rheumatic or congenital heart diseases were excluded. LV lead placement was concordant in 22 (46.8%) cases. After the follow-up period, 31 (65.9%) of the study population were considered volumetric responders with no significant difference among both groups (14 (63.3%) in group A vs 17 (68%) in group B, p > 0.05). CRT insertion resulted in significant improvement of NYHA class in 36 (76.5%) cases, 6-min walk test (447.2 ± 127.0 vs 369.6 ± 87.5m, p < 0.01), MLHFQ (58.1 ± 19.7 vs 69.6 ± 13.5, p < 0.01), QRS duration (131.2 ± 13.8 vs 149.4 ± 16msec, p < 0.01), 2D LV EF 33.0 ± 9.5 vs 25.3 ± 6.5, p < 0.001), LVESV (156.0 ± 82.9 vs177.6 ± 92.7ml, p < 0.05), and 3D LVEF (29.1 ± 9.0 vs 23.6 ± 5.9, p < 0.001) irrespective of the etiology of heart failure. However, there were no significant differences between both groups regarding the same parameters (6-min walk test 470.8 ± 128.7 vs 428.3 ± 126.8m, MLHFQ 56.8 ± 20.0 vs 58.11 ± 19.0, QRS duration 129.9 ± 12.4 vs 132.1 ± 15.1msec, 2D LVEF 30.9 ± 8.3 vs 34.58 ± 10.9, LVESV 173.0 ± 110.0 vs 143.0 ± 67.9, 3D LVEF 26 ± 8 vs 31 ± 9, for groups A and B, respectively, p < 0.05). Standard anatomical LV lead placement remains a simple, practical, and effective method in patients undergoing CRT. 3D echocardiography-guided LV lead placement added no clinical benefit compared to standard techniques.