Cardiac resynchronization therapy (CRT) is an established treatment for left bundle branch block (LBBB) resulting in mechanical dyssynchrony. Approximately 1/3 of patients with CRT, however, are non-responders. To understand factors affecting CRT response, an electromechanics-perfusion computational model based on animal-specific left ventricular (LV) geometry and coronary vascular networks located in the septum and LV free wall is developed. The model considers contractility-flow and preload-activation time relationships, and is calibrated to simultaneously match the experimental measurements in terms of the LV pressure, volume waveforms and total coronary flow in the left anterior descending and left circumflex territories from 2 swine models under right atrium and right ventricular pacing. The model is then applied to investigate the responses of CRT indexed by peak LV pressure and (dP/dt)max at multiple pacing sites with different degrees of perfusion in the LV free wall. Without the presence of ischemia, the model predicts that basal-lateral endocardial region is the optimal pacing site that can best improve (dP/dt)max by 20%, and is associated with the shortest activation time. In the presence of ischemia, a non-ischemic region becomes the optimal pacing site when coronary flow in the ischemic region fell below 30% of its original value. Pacing at the ischemic region produces little response at that perfusion level. The optimal pacing site is associated with one that optimizes the LV activation time. These findings suggest that CRT response is affected by both pacing site and coronary perfusion, which may have clinical implication in improving CRT responder rates. •A novel electromechanics-perfusion computational model based on animal-specific geometry and measurements is developed.•The relationship between contractility and myocardial perfusion is considered.•The calibrated model is applied to optimize cardiac resynchronization therapy (CRT) response.•The effects of pacing site and degree of coronary perfusion on CRT response are investigated.