Abstract Funding Acknowledgements The study was supported by Center for Cardiological Innovation. Introduction Septal dysfunction is the dominant mechanism of left ventricular (LV) failure in left bundle branch block (LBBB). We hypothesize that, provided septum is viable, septal function can recover and hence LV function improve after cardiac resynchronization therapy (CRT). Purpose To determine if combined assessment of septal function and viability identifies responders to CRT. Methods In a prospective multicenter study of 200 unselected patients referred for CRT, we measured myocardial strain by speckle-tracking echocardiography and regional work by pressure-strain analysis before and 7 ± 1 months after CRT. Viability was assessed by late gadolinium enhancement cardiac magnetic resonance imaging (n = 123). CRT response was defined as ≥15% reduction in LV end-systolic volume. Results Before CRT, septal work was 258 ± 463 and LV lateral wall work 1469 ± 674 mmHg·% (p < 0.0001). In CRT responders, septal work was restored to 1243 ± 495 mmHg·%, whereas non-responders showed less marked improvement (p < 0.0001). The figure illustrates a typical CRT responder with negative septal work and a large difference between work in the LV lateral wall and septum (panel A). There was no septal scar (panel B) and, after 6 months with CRT, septal work was recovered (panel C). Pressure-strain loops illustrate that CRT converted inefficient septal contractions with substantial negative (wasted) work to positive work throughout systole. For the entire study population, the difference between work in the LV lateral wall and septum predicted CRT response with area under the curve (AUC) 0.75 (95% CI: 0.68-0.83) and was feasible in 98% of patients. Furthermore, septal scar predicted non-response to CRT with AUC 0.76 (95% CI: 0.65-0.86). Combining work difference and septal viability improved AUC for CRT response to 0.85 (95% CI: 0.76-0.94) (figure panel D). The AUC was similar for QRS 120-150 and >150 ms. Conclusions The proposed combined approach with assessment of septal work and viability identified CRT responders with high precision. Abstract 561 Figure.