Isothermal calorimeter was used to determine the integral heat of water vapor sorption directly on human native, delipidized and water washed delipidized SC at 32ºC as a function of relative humidity (RH), using back and thigh skin from three different donors. Calorimetric measurements were combined with water vapor sorption measurements to determine the thermodynamic properties of these systems. Conformations changes in the keratin and intercellular lipids were investigated using Attenuated Total Reflection-Fourier Transform Infrared (ATR-FTIR) Spectroscopy. The differential enthalpy and entropy of water sorption in SC and its component are consistent with a model in which water first binds tightly to polar sites on keratin, replacing keratin-keratin bonds with energetically favorable keratin-water bonds. This process which results in swelling, leads to rapid decreases in the magnitudes of the differential thermodynamic properties ( and ) with increasing water content. Plots of versus exhibit entropy-enthalpy compensation a phenomenon frequently observed in protein/water interactions. Extraction of SC lipids with Chloroform/Methanol led to much reduced binding enthalpy at low water content, while binding free energy was changed much less. Water extraction of delipidized SC had a little additional effect on binding enthalpy. FTIR spectra results are consistent with those obtained from calorimetric thermodynamic analysis and indicate that conformational changes accompanying lipid removal alter the strength of protein-water interactions.