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Introduction: Cardiac resynchronization defibrillator (CRT‐D) as primary prevention is known to reduce mortality. At the time of replacement, higher age and comorbidities may attenuate the benefit of implantable cardioverter‐defibrillator (ICD) therapy. The purpose of this study was to evaluate the progression of comorbidities after implantation and their association with mortality following CRT‐D generator replacement. In addition, a risk score was developed to identify patients at high risk for mortality after replacement. Methods and Results: We identified patients implanted with a primary prevention CRT‐D (n = 648) who subsequently underwent elective generator replacement (n = 218) from two prospective ICD registries. The cohort consisted of 218 patients (median age: 70 years, male gender: 73%, mean left ventricular ejection fraction [LVEF]: 36 ± 11% at replacement). Median follow‐up after the replacement was 4.2 years during which 64 patients (29%) died and 11 patients (5%) received appropriate ICD shocks. An increase in comorbidities was observed in 77 patients (35%). The 5‐year mortality rate was 41% in patients with ≥2 comorbidities at the time of replacement. A risk score incorporating age, gender, LVEF, atrial fibrillation, anemia, chronic kidney disease, and history of appropriate ICD shocks at time of replacement accurately predicted 5‐year mortality (C‐statistic 0.829). Patients with a risk score of greater than 2.5 had excess mortality at 5‐year postreplacement compared with patients with a risk score less than 1.5 (57% vs. 6%; p <.001). Conclusion: A simple risk score accurately predicts 5‐year mortality after replacement in CRT‐D patients, as patients with a risk score of greater than 2.5 are at high risk of dying despite ICD protection. [ABSTRACT FROM AUTHOR]