Purpose: To assess the use and validity of a mean systemic filling pressure analogue (Pmsa) in the closedloop control of fluid replacement in continuous hemodiafiltration. Methods: Cardiovascular variables were computer acquired from bedside monitor. Pmsa was calculated and compared with a target value. Gravitational fluid replacement to the extracorporeal hemodiafiltration circuit was regulated with a computer-controlled clamp. Results: Ten patients (mean acute physiology and chronic health evaluation II score, 29.7; range, 21-33) received continuous venovenous hemodiafiltration for acute renal failure. Fluid replacement therapy was closed loop controlled to a target Pmsa for a total of 601 hours. During this period, 417 L of ultradiafiltrate were lost, and 409 L of replacement and nutritional fluids were administered. Despite such large fluid shifts, measured hemodynamic variables were kept within a narrow range (hour to hour variability: right atrial pressure, 1 ± 0.1 mm Hg; mean arterial pressure 5.9 ± 0.5 mm Hg; cardiac index, 0.44 ± 0.05 L/m2/min). No complications of the technique occurred. Conclusions: The stability of cardiovascular variables achieved during Pmsa-based fluid replacement of critically ill patients with major fluid losses supports the validity of the use of the Pms, as a measure of intravascular volume status. Such an analogue may be useful in nondialytic environments. The use of Pmsa as the basis for automated fluid replacement was safe.