The presence of negatively charged, impermeant proteins in the plasma space alters the distribution of diffusible ions in the plasma and interstitial fluid (ISF) compartments to preserve electroneutrality. We have derived a new mathematical model to define the quantitative interrelationship between the Gibbs-Donnan equilibrium, the osmolality of body fluid compartments, and the plasma water Na+ concentration ([Na+]pw) and validated the model using empirical data from the literature. The new model can account for the alterations in all ionic concentrations (Na+ and non-Na+ ions) between the plasma and ISF due to Gibbs-Donnan equilibrium. In addition to the effect of Gibbs-Donnan equilibrium on Na+ distribution between plasma and ISF, our model predicts that the altered distribution of osmotically active non-Na+ ions will also have a modulating effect on the [Na+]pw by affecting the distribution of H2O between the plasma and ISF. The new physiological insights provided by this model can for the first time provide a basis for understanding quantitatively how changes in the plasma protein concentration modulate the [Na+]pw. Moreover, this model defines all known physiological factors that may modulate the [Na+]pw and is especially helpful in conceptually understanding the pathophysiological basis of the dysnatremias.