Entropy (ENT) is a newly developed measure of the complexity of heart rate variability (HRV). The aim of this study was to characterize the complexity of HRV in patients with end-stage renal disease (ESRD) and to find a possible clinical utility. Healthy subjects and patients with ESRD undergoing hemodialysis (HD) were recruited. The HD population consisted of patients with and without diabetes mellitus (DM). An electrocardiogram was recorded before HD, and blood pressure was measured during HD. The coefficients of variation of R-R intervals, high- and low-frequency components, and ratio of the low- to high-frequency components were measured as variables of HRV. The ENT was used to describe the complexity of HRV. Forty-six healthy subjects and 27 HD patients participated in this study. The ENT negatively correlated with the duration of DM (p = 0.001), systolic blood pressure (p = 0.003), and mean blood pressure (p = 0.004) before a HD session. ENT in HD patients was lower than that in healthy subjects (p < 0.01). ENT in HD patients with DM was lower than that in HD patients without DM (p < 0.01). The change in systolic blood pressure (DeltaSBP) during a HD session showed high correlations to ENT and ultrafiltration rate (UFR) of the dialyzer. The following equation was obtained: DeltaSBP = 2.25 x ENT - 2.28 x UFR - 21.27 (R2 = 0.805; p < 0.0001). ENT decreased with uremic and diabetic status. ENT also represents a possible prediction of hypotension during a HD session.