The presence of negatively charged, impermeant proteins in the plasma space alters the distribution of diffusible ions in the plasma and interstitial fluid compartments in order to preserve electroneutrality and is known as Gibbs-Donnan equilibrium. In patients with hypoalbuminemia due to underlying cirrhosis, the decrease in the plasma water albumin concentration ([Alb^–]_pw) would be expected to result in a decrease in the plasma water sodium concentration ([Na⁺]_pw) due to an alteration in the distribution of Na+ ions between the plasma and ISF. In addition, cirrhosis-associated hyponatremia may be due to the renal diluting defect resulting from the intravascular volume depletion due to gastrointestinal losses and overdiuresis and/or decreased effective circulatory volume secondary to splanchnic vasodilatation. Therefore, albumin infusion may result in correction of the hyponatremia in cirrhotic patients either by modulating the Gibbs-Donnan effect or by restoring intravascular volume in patients with intravascular volume depletion. However, the differential role of albumin infusion in modulating the [Na⁺]_pw in these patients has not previously been analyzed quantitatively. In the present study, we developed an in vitro assay system to examine the quantitative effect of changes in [Alb^–] on the distribution of Na⁺ ions between two compartments separated by a semipermeable membrane. Our findings demonstrated that changes in [Alb^–]pw are linearly related to changes in Na⁺]_pw as predicted by Gibbs-Donnan equilibrium. However, based on our findings, we predict that the improvement in cirrhosis-associated hyponatremia due to intravascular volume depletion results predominantly from the restoration of intravascular volume rather than alterations in Gibbs-Donnan equilibrium.