Traditional indexes of LV dyssynchrony (DYS) in pts to be resynchronized are sensitive to noise, while the concordance between LV lead position and site of latest mechanical activation is suggested to be, in these patients, clinically relevant. Both aspects, asynchrony and lead position have been addressed separately but unclear is their potential synergistic role in the clinical evolution of CRT patients. We assessed clinical and echocardiographic outcome, as well as mid-term prognosis, in a population of CHF patients submitted to CRT, stratified according to a novel asynchrony quantitation (temporal uniformity of strain: TUS) method and concordance or not between presumed LV lead position and site of latest mechanical activation. TUS was computed in 85 pts (QRS > 120 ms, EF < 0.35) in whom we measured circumferential and longitudinal strains using speckle-tracking 2D-echocardiography before and 3-6 months after CRT, together with triplane apical LV volumes. Optimal LV lead position in short axis view was defined as concordance of the segment with latest systolic circumferential strain prior-CRT and segment with assumed LV lead position. Assumed LV lead position was defined from a chest X-ray obtained 1 day after implantation and scored as anterior, lateral, posterior or inferior using 2 orthogonal views (antero-posterior and lateral). Following CRT, LV volume decreased (diastolic -8 ± 20%) and EF improved (+6 ± 9%, P < 0.001 for both). Two-way ANOVA revealed TUS improvement post-CRT (+22 ± 68%, P = 0.025), with a clear evidence for more marked asynchrony detectable at circumferential (from 0.53 ± 0.20 to 0.55 ± 0.19) as compared with longitudinal level (from 0.56 ± 0.14 to 0.62 ± 0.14) (P = 0.017). Multivariate analysis revealed that greater baseline asynchrony, as assessed circumferentially (P = 0.079), together with concordance between LV lead position and site of activation (P = 0.012), besides younger age (P = 0.051), longer QRS duration (P = 0.021) and higher baseline EF (P = 0.04),), but not longitudinal TUS (P = 0.231) did predict death from any cause or new episodes of pulmonary or systemic congestion requiring i.v. diuretics during a 529 ± 357 days clinical follow-up. We conclude that DYS indexed by circumferential TUS yields CRT benefits, supporting the idea of targeting TUS-measured DYS as the informative asynchrony quantitative measurement in CRT pts. Significant predictability in medium-term clinical follow-up of patients to be resynchronized is also associated with concordance between site of latest mechanical activation and presumed LV lead position in the present study.