BACKGROUND: Although cardiac resynchronization therapy (CRT) can improve left ventricular ejection fraction (LVEF), it is not known whether a specific level of improvement will predict future implantable cardioverter defibrillator (ICD) therapy. METHODS AND RESULTS: CRT-defibrillator (CRT-D) was implanted in 423 patients at 1 institution between October 2, 2001 and January 19, 2007. A retrospective analysis was performed to evaluate the relationship between post-CRT-D LVEF and ICD therapy for ventricular tachyarrhythmias. A landmark population of 270 patients, with post-CRT-D LVEF measured and no ICD therapy within 1 year of device implantation, was followed for subsequent outcomes. Of these, 22 patients (8.2%) had subsequent appropriate ICD therapy over a median follow-up of 1.5 years. The estimated 2-year risk of appropriate ICD therapy is 3.0% (95% confidence interval [95% CI], 0%-6.3%), 2.1% (95% CI, 0%-5.0%), and 1.5% (95% CI, 0%-3.9%) for post-CRT-D LVEF of 45%, 50%, and 55%, respectively. In patients with a primary prevention indication for CRT-D, the estimated 2-year risk is 3.3% (95% CI, 0%-7.3%), 2.5% (95% CI, 0%-6.1%), and 1.9% (95% CI, 0%-5.1%) for post-CRT-D LVEF of 45%, 50%, and 55%, respectively. CONCLUSIONS: When a CRT responder demonstrates near normalization in LVEF to ≥45%, the incidence of ICD therapy for ventricular arrhythmias becomes low. Future studies are needed to determine whether an ICD is still needed in some of these patients at the time of generator replacement.