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The identification of responders to cardiac resynchronization therapy (CRT) remains a challenge. We assessed the role of dyssynchrony (DYS) and contractile reserve (CR) in identifying CRT responders.Sixty-nine patients (55% with ischaemic aetiology) referred for CRT (ejection fraction ≤35%, New York Heart Association ≥III, and QRS duration ≥120 ms) underwent baseline evaluation of DYS and dobutamine stress-echo [up to 40 µg/kg/min: CR was defined as a wall motion score index (WMSI) variation ≥0.20]. CRT responders were identified by clinical and/or echocardiographic [end-systolic volume (ESV) decrease ≥15%] follow-up criteria. During a median follow-up of 11 months, 46 patients (66%) were classified as clinical responders. Reverse remodelling was found in 34 of the 59 patients (58%) with echocardiographic follow-up. CR was present in 78% of clinical responders (P = 0.001) and in 69% with reverse remodelling (P = 0.005). DYS was equally present in the two groups. Reverse remodelling was correlated with rest–stress changes in ESV (r = 0.439, P = 0.003) and in WMSI (r = 0.450, P = 0.001), but not with DYS. CR (OR = 6.2, 95% CI = 1.4–27.6, P = 0.015) was the best predictor of response to CRT.Patients with CR show a favourable clinical and reverse LV remodelling response to CRT. This finding shifts the focus from electrical (dyssynchrony) to the myocardial substrate of functional response.