BACKGROUND: Stroke and low heart rate variability (HRV) are both associated with an unfavorable prognosis in hemodialysis patients. The relationship between stroke and changes in HRV during hemodialysis remains unclear. METHODS: This study measured differences between predialysis and postdialysis HRV ( big up tri, openHRV) in 182 maintenance hemodialysis patients, including 30 patients with stroke, to assess changes in HRV during hemodialysis, and also to compare results to 114 healthy controls. RESULTS: All predialysis HRV measurements had no differences between stroke patients and those without stroke, but were lower than healthy controls. Postdialysis very low frequency (VLF) (P < 0.001), low frequency (LF) (P = 0.001), total power (TP) (P < 0.001) and the LF/high frequency (HF) ratio (P < 0.001) increased significantly relative to predialysis values in patients without stroke, whereas postdialysis HRV did not increase in stroke patients. After multivariate adjustment, dialysis vintage was negatively associated with big up tri, openVLF (beta = -0.698, P = 0.046), big up tri, openLF (beta = -0.931, P = 0.009), and big up tri, openTP (beta = -0.887, P = 0.012) in patients without stroke. Serum intact parathyroid hormone (beta = -0.707, P = 0.019) was negatively associated with big up tri, openLF. Total cholesterol (beta = -0.008, P = 0.001) and high sensitivity C-reactive protein (beta = -0.474, P = 0.012) were inversely correlated with the big up tri, openLF/HF ratio in patients without stroke. CONCLUSION: HRV in hemodialysis patients is lower than in the general population. Increase in big up tri, openHRV was observed in hemodialysis patients without stroke but not in stroke patients. This result suggests suppressed autonomic nervous reactions against volume unloading during hemodialysis, which might contribute to unfavorable outcomes in hemodialysis patients but even more so in those with prior stroke. Nephrologists should notice the importance of big up tri, openHRV especially in high-risk patients.