The stratum corneum (SC) is an important biological barrier retarding both water loss from the body and the absorption of hazardous materials from the environment. Isothermal calorimetry is a tool with which one can develop thermodynamic data regarding the affinity of water and solvents for this tissue; this information is central to the interpretation of the equilibrium uptake of water and is indirectly related to skin permeability, which changes as the tissue swells. A thermodynamic study of water interaction with human skin is presented. The procedure consisted of conjoint vapor adsorption and heat flow measurements. The heat of sorption of water in excised human SC at various relative humidities was measured at 32˚C using skin samples from multiple donors. These measurements, combined with the water vapor sorption isotherm, were used to calculate the integral and differential enthalpies of binding of water to SC. A kinetic model was developed to express heat and water vapor sorption for the SC–water interactions as functions of time and relative humidity. A finite difference method was used to solve the non-linear differential equations that describe coupled heat and mass transfer in human SC. This solution was validated by comparing simulation results with corresponding experimental data for the heat of water vapor sorption on human skin.