Pseudohyponatremia is a clinical condition characterized by an increased fraction of protein or lipid in plasma, thereby resulting in an artificially low plasma sodium concentration ([Na⁺]_p). Since the automated method of measuring [Na⁺]_p in most laboratories involves the use of an indirect ion-selective electrode (I-ISE), this method does not correct for elevated protein or lipid concentrations. In I-ISE, the plasma sample is diluted before the actual measurement is obtained, and the [Na⁺]_p is determined based on the assumption that plasma is normally composed of 93% plasma water. Therefore, the [Na⁺]_p as determined by I-ISE will be artificially low in clinical conditions when the plasma water content (PWC) is less than 93%. In contrast, the plasma is not diluted when the [Na⁺]_p is measured using direct ISE (D-ISE). This method directly measures Na⁺ activity in plasma water and is therefore unaffected by the proportion of plasma occupied by water. In this study, we report a novel quantitative method for determining the PWC utilizing I-ISE and D-ISE. To validate this new method experimentally, we altered the PWC in vitro by dissolving varying amount of salt-free albumin in human plasma. We then measured PWC gravimetrically in each sample and compared the gravimetrically determined PWC with the ISE-determined PWC. Our findings indicate that the PWC can be accurately determined based on differences in the [Na⁺]_p as measured by I-ISE and D-ISE and that this new quantitative method can be a useful adjunct in the analysis of the dysnatremias.