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Age is an adverse prognostic factor in patients with heart failure. We aimed to assess the impact of age and noncardiac co-morbidities in the outcome of patients undergoing cardiac resynchronization therapy (CRT), and determine which of these two factors is the most important predictor of survival. The study involved a single-center retrospective assessment of 697 consecutive CRT implants during a 12-year period. Patient co-morbidity profile was assessed using the Charlson Co-morbidity Index (CCI) and the Charlson Age-Co-morbidity Index (CACI). Predictors of survival free from heart transplantation were assessed. CRT-related complications and cause of death analysis were assessed within tertiles of the CACI. During a mean follow-up of 1,813 ± 1,177 days, 347 patients (49.9%) died and 37 (5.3%) underwent heart transplantation. On multivariate Cox regression, female gender (HR = 0.78, 95% confidence interval [CI] 0.62 to 0.99, p = 0.041), estimated glomerular filtration rate (HR per ml/min = 0.99, 95% CI 0.98 to 0.99, p < 0.001), left ventricular ejection fraction (HR per % = 0.99, 95% CI 0.98 to 1.00, p = 0.022), New York Heart Association class (HR = 1.83, 95% CI 1.53 to 2.20, p < 0.001), presence of left bundle branch block (HR = 0.70, 95% CI 0.56 to 0.87, p = 0.001), and CACI tertile (HR = 1.37, 95% CI 1.18 to 1.59, p < 0.001) were independent predictors of all-cause mortality or heart transplantation. Compared with age and the CCI, the CACI was the best discriminator of all-cause mortality. Inappropriate therapies occurred less frequently in higher co-morbidity tertiles. In conclusion, patient co-morbidity profile adjusted to age impacts on mortality after CRT implantation. Use of the CACI may help refine guideline criteria to identify patients more likely to benefit from CRT., (Copyright © 2017 Elsevier Inc. All rights reserved.)