The Stratum Corneum (SC) is an important biological barrier retarding both water loss from the human body and the absorption of hazardous materials from the environment. Isothermal calorimetry is a powerful tool to obtain thermodynamic data regarding the affinity of water for SC. This information is central to the interpretation of equilibrium uptake of water, and is indirectly related to skin permeability, which changes as the tissue swells. Isothermal flow calorimetry was used to determine the integral heat of water sorption on human SC, delipidized SC, and water-washed delipidized SC at 32ºC as a function of relative humidity. SC was obtained from three different donors, from the back and thigh. The calorimetric data were combined with water-vapor sorption measurements to determine the thermodynamic properties of the system. The differential enthalpy and entropy of water sorption in SC are consistent with a mechanism in which water first binds tightly to polar sites on keratin, replacing keratin-keratin bonds with energetically favorable keratin-water bonds. This process swells and softens the tissue, leading to rapid decreases in the magnitudes of the differential thermodynamic properties with increasing water content. The experimental measurements were analyzed with a multilayer heat of sorption equation derived from the Guggenheim-Anderson-deBoer (GAB) model; this equation is similar in principle to the GAB water-sorption equation. The experimental water vapor and heat of sorption isotherms were successfully described by multilayer GAB model. It will be shown that the pre-exponential factors of adjustable parameters of the GAB model are different from unity; these have previously been assumed in the literature as unity.