Background It has been argued that the benefits of reducing sodium loading may be offset by increased activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system. This study aimed to investigate the long-term effects of an increase in dialysis sodium removal on circulating RAAS and sympathetic system in hypertensive hemodialysis (HD) patients with "normal" post-HD volume status. Methods Thirty hypertensive HD patients were enrolled in this pilot trial. After one month period of dialysis with standard dialysate sodium of 138 mmol/L, the patients were followed up for a four months period with dialysate sodium set at 136 mmol/L, without changes in instructions regarding dietary sodium control. During the period of study, the dry weight was adjusted monthly under the guidance of bioimpedance spectroscopy to maintain post-HD volume status in a steady state; 44-hour ambulatory blood pressure, plasma renin, angiotensin II (Ang II), aldosterone, and norepinephrine (NE) were measured. Results After four months of HD with low dialysate sodium of 136 mmol/L, 44-hour systolic and diastolic blood pressures (BPs) were significantly lower (-10 and -6 mmHg), in the absence of changes in antihypertensive medications. No significant changes were observed in plasma renin, Ang II, aldosterone, and NE concentrations. The post-HD volume parameters were kept constant. Conclusion Mildly increasing dialysis sodium removal over 4 months can significantly improve BP control and does not activate circulating RAAS and sympathetic nervous system in hypertensive HD patients.