OBJECTIVES: This study sought to evaluate the prognostic value of heart rate variability (HRV) for death or heart failure in patients with mildly symptomatic heart failure undergoing cardiac resynchronization therapy with a defibrillator (CRT-D). BACKGROUND: There are limited data regarding the prognostic value of HRV as a means of identifying high-risk patients treated with CRT-D. METHODS: We analyzed the relationship between pre-implant time-domain (SD of all normal-to-normal RR intervals [SDNN], SDs of averaged 5-min normal-to-normal RR intervals, root mean square of successive differences, and mean of the SDs of all normal-to-normal RR intervals for all 5-min segments of the entire recording), and frequency-domain (low-frequency power, very-low-frequency power [VLF], high-frequency power, low-frequency power/low-frequency power ratio) HRV parameters, and the end point of death or heart failure and death alone. Study subjects include 719 patients in normal sinus rhythm enrolled in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy); outcomes of CRT-D patients with low HRV (lower tertile) were compared with CRT-D patients with preserved HRV (2 upper tertiles) and with patients receiving implantable cardioverter-defibrillators only. RESULTS: During a mean 3.4 +/- 0.9 years of follow-up, 124 patients reached the primary end point of death or heart failure, and 47 died. In multivariate analysis, low SDNN (</=93 ms) was associated with significantly higher risk of death or heart failure (hazard ratio [HR] 1.63 [95% confidence interval (CI): 1.12 to 2.36]; p = 0.010) and mortality (HR 2.10 [95% CI: 1.14 to 3.87]; p = 0.017) compared with higher SDNN (>93 ms). Similarly, low VLF (</=179 ms(2)) was associated with an increased risk of death or heart failure (HR 2.14 [95% CI: 1.46 to 3.13]; p < 0.001) and death alone (HR 2.49 [95% CI: 1.35 to 4.57]; p = 0.003). There was no significant difference in outcome between low HRV patients treated with CRT-D and patients receiving an implantable cardioverter-defibrillator only. CONCLUSIONS: Our findings indicate that autonomic dysfunction (quantified by low SDNN and low VLF) identified patients with no benefit or limited benefit from cardiac resynchronization therapy. Pre-implant HRV analysis might help in optimizing qualifications for this treatment.