The enhancement of ribonuclease A (RNAase) thermostability in water-immiscible organic solvents with respect to water has been studied by differential scanning calorimetry (DSC) and IR spectroscopy. RNAase has been adsorbed onto an inert support (Celite) in order to avoid aggregation effects. The dependence on hydration of the thermodynamic parameters of unfolding, such as the enthalpy change, Delta H, and the transition temperature, Tm, have been studied in the absence of any solvent and in the presence of selected water-immiscible organic solvents. In both cases, RNAase shows a progressive enhancement of the thermal stability as the water content is lowered. In highly hydrophobic solvents, RNAase stability does not change significantly with respect to the no-solvent state at the same hydration level. More hydrophilic solvents enhance stability by further dehydrating the protein molecule. A correlation has been found between the protein stability parameters (Delta H and Tm) and the dielectric constant of the bulk solvent, suggesting that electrostatic interactions may play a relevant role in protein stability in aqueous solution. A poorer correlation was found with solvent hydrophobicity indexes, such as log P. The presence of organic solvent perturbs the IR spectra of the denatured RNAase more significantly than the corresponding spectra of the thermally native protein.