The thermodynamics of interaction between poly(perfluorosulfonic acid) Nafion and water is studied by isothermal sorption and microcalorimetry. The concentration dependences of energy and entropy parameters of mixing of Nafion aqueous solutions are determined. It is shown that the Gibbs energy and the enthalpy of mixing are negative while the entropy of mixing is positive over the entire range of solution compositions. The experimental water sorption isotherms and the concentration dependences of the enthalpy of dilution of aqueous solutions are analyzed in terms of the thermodynamic model allowing for pair nonvalence interactions in solution, nonequilibrium glassy structure of the polymer, and effects of the dissociation of ionic sulfo groups of Nafion. The calculated value of the Flory–Huggins parameter is 1.48, and the value of its enthalpy component is close to zero.