Objectives: The study was designed to develop a simple risk stratification score for primary therapy with an implantable cardioverter-defibrillator (ICD). Background: Current guidelines recommend primary ICD therapy in patients with a low ejection fraction (EF). However, the benefit of the ICD in the low EF population may not be uniform. Methods: Best-subset proportional-hazards regression analysis was used to develop a simple clinical risk score for the end point of all-cause mortality in patients allocated to the conventional therapy arm of MADIT (Multicenter Automatic Defibrillator Implantation Trial)-II after excluding a pre-specified subgroup of very high-risk (VHR) patients (defined by blood urea nitrogen [BUN] ≥50 mg/dl and/or serum creatinine ≥2.5 mg/dl). The benefit of the ICD was then assessed within risk score categories and separately in VHR patients. Results: The selected risk score model comprised 5 clinical factors (New York Heart Association functional class >II, age >70 years, BUN >26 mg/dl, QRS duration >0.12 s, and atrial fibrillation). Crude mortality rates in the conventional group were 8% and 28% in patients with 0 and ≥1 risk factors, respectively, and 43% in VHR patients. Defibrillator therapy was associated with a 49% reduction in the risk of death (p < 0.001) among patients with ≥1 risk factors (n = 786), whereas no ICD benefit was identified in patients with 0 risk factors (n = 345; hazard ratio 0.96; p = 0.91) and in VHR patients (n = 60; hazard ratio 1.00; p > 0.99). Conclusions: Our data suggest a U-shaped pattern for ICD efficacy in the low-EF population, with pronounced benefit in intermediate-risk patients and attenuated efficacy in lower- and higher-risk subsets.