BACKGROUND: In patients with renal failure on hemodialysis cardiovascular disease is a major cause of death. It has been reported that diminished heart rate variability (HRV) relates to the unfavorable prognosis in post-infarction and/or heart failure patients. However, the prognostic value of HRV in hemodialysis patients has not been fully established. METHODS AND RESULTS: Time- and frequency-domain analysis of HRV on 24-hour ambulatory electrocardiography recording was assessed prospectively in 383 chronic hemodialysis patients (220 men and 163 women, mean age 57+/-13 years, ejection fraction 65+/-12%). During 2110+/-903 days of follow up, 146 patients died (31 congestive heart failure, 13 fatal myocardial infarction, 13 sudden deaths, 26 stroke, and 63 non-cardiovascular deaths). A Cox univariate analysis identified the following factors as predictors of both all-cause and cardiovascular death: age, gender, ejection fraction, presence of diabetes, and HRV parameters calculated in the time- and frequency-domain. In multivariate analysis, a low standard deviation of all normal RR intervals (SDNN) value was the strongly associated with both all-cause and cardiovascular death (hazard ratios [95% confidence intervals] 0.988 [0.982-0.994] and 0.984 [0.974-0.993], respectively). From Kaplan-Meier survival curves, the incidence of all-cause and cardiovascular death was much greater in patients with a low SDNN (<75 msec), even after adjusting for the presence of diabetes (P<0.0001). CONCLUSIONS: Decreased HRV on 24-hour ambulatory electrocardiography is an independent predictor of mortality in chronic hemodialysis patients.