Abstract Objectives This study sought to test the hypothesis that end-systolic volume (ESV), as a marker of severity of left ventricular (LV) remodeling, influences the relationship between myocardial viability and survival in patients with coronary artery disease and LV systolic dysfunction. Background Retrospective studies of ischemic LV dysfunction suggest that the severity of LV remodeling determines whether myocardial viability predicts improved survival with surgical compared with medical therapy, with coronary artery bypass grafting (CABG) only benefitting patients with viable myocardium who have smaller ESV. However, this has not been tested prospectively. Methods Interactions of end-systolic volume index (ESVI), myocardial viability, and treatment with respect to survival were assessed in patients in the prospective randomized STICH (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease) trial of CABG versus medical therapy who underwent viability assessment (n = 601; age 61 ± 9 years; ejection fraction ≤35%), with a median follow-up of 5.1 years. Median ESVI was 84 ml/m2 . Viability was assessed by single-photon emission computed tomography or dobutamine echocardiography using pre-specified criteria. Results Mortality was highest among patients with larger ESVI and nonviability (p < 0.001), but no interaction was observed between ESVI, viability status, and treatment assignment (p = 0.491). Specifically, the effect of CABG versus medical therapy in patients with viable myocardium and ESVI ≤84 ml/m2 (hazard ratio HR: 0.85; 95% confidence interval CI: 0.56 to 1.29) was no different than in patients with viability and ESVI >84 ml/m2 (HR: 0.87; 95% CI: 0.57 to 1.31). Other ESVI thresholds yielded similar results, including ESVI ≤60 ml/m2 (HR: 0.87; 95% CI: 0.44 to 1.74). ESVI and viability assessed as continuous rather than dichotomous variables yielded similar results (p = 0.562). Conclusions Among patients with ischemic cardiomyopathy, those with greater LV ESVI and no substantial viability had worse prognosis. However, the effect of CABG relative to medical therapy was not differentially influenced by the combination of these 2 factors. Lower ESVI did not identify patients in whom myocardial viability predicted better outcome with CABG relative to medical therapy. (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease STICH; NCT00023595 )