Extracellular fluid volume (ECFV) expansion in hemodialysis patients is associated with increased mortality. Attempts to remove excess fluid often result in intradialytic hypotension (IDH). Blood volume monitoring has been used to aid selection of ultrafiltration rates and dialysate conductivity to minimize IDH. Automating ultrafiltration and dialysate conductivity using the Hemocontrol Biofeedback System (HBS) has reduced IDH in IDH-prone subjects. We undertook a randomized controlled trial to determine if the HBS could safely reduce ECFV in ECF-expanded subjects. Patients with ECFV >45% of total body water were randomized to receive hemodialysis by either HBS or best clinical practices for 6 months. The primary endpoint was change in ECFV; exploratory variables included frequency of IDH, interdialytic weight gain, and changes in serum Na. Treatment with HBS did not result in any change in ECFV, even after multivariable adjustment. The frequency of IDH was however significantly lower with HBS when compared with best clinical practices without differences in other variables.