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BACKGROUND Global electrical heterogeneity (GEH) is associated with sudden cardiac death in the general population. Its utility in patients with systolic heart failure (HF) who are candidates for primary prevention (PP) implantable cardioverter-defibrillators (ICDs) is unclear. OBJECTIVE To investigate whether GEH is associated with sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) leading to appropriate ICD therapies in HF patients with PP ICDs. METHODS We conducted a multicenter retrospective cohort study. GEH was measured by spatial ventricular gradient (SVG) direction (azimuth and elevation) and magnitude, QRS-T angle, and sum absolute QRST integral (SAIQRST) on pre-implant 12-lead ECGs. Survival analysis using cause-specific hazard functions compared the strength of associations with two competing outcomes: sustained VT/VF leading to appropriate ICD therapies and all-cause death without appropriate ICD therapies. RESULTS We analyzed 2,668 patients (age 63±12y; 23% female; 78% white; 43% nonischemic cardiomyopathy (NICM); left ventricular ejection fraction 28±11% from 6 academic medical centers). After adjustment for demographic, clinical, device, and traditional ECG characteristics, SVG elevation (Hazard Ratio (HR) per 1 standard deviation (SD) 1.14 (95% CI 1.04-1.25); P=0.004), SVG azimuth (HR per 1 SD 1.12(1.01-1.24); P=0.039); SVG magnitude (HR per 1 SD 0.75(0.66-0.85); P<0.0001), and QRS-T angle (HR per 1 SD 1.21 (95% CI 1.08-1.36); P=0.001) were associated with appropriate ICD therapies. SAIQRST had different associations in infarct-related [HR 1.29(1.04-1.60)] and NICM [HR 0.78(0.62-0.96); Pinteraction=0.022]. CONCLUSION In patients with PP ICDs, GEH is independently associated with appropriate ICD therapies. The SVG vector points in distinctly different directions in patients with two competing outcomes.