Interactions of Nafion (Naf) ionomer with water, aqueous ethanol (EA), aqueous isopropyl alcohol (IPA), and aqueous ammonia were investigated by attenuated total reflectance (ATR)–infrared (IR) spectroscopy, differential scanning calorimetry, thermogravimetric analysis, and computational modeling studies. Microstructural features by ATR–IR revealed the existence of hydrophilic interaction of Naf with all solvents. The Naf membranes formed hydrogen bonds with water, aqueous EA, and IPA. The incorporation of solvents on the Naf matrix impaired the crystallinity, which was highest in the case of IPA. Of all the microsolvated structures of Naf investigated, the formation of H3O+ ions was evident; in addition, H5O2+ ions appeared in the alcohol–water mixture, and NH4+ ions were observed in the water–ammonia mixture along with a direct ion pair with the SO3− group in Naf. Theoretical studies based on computational modeling disclosed that the interchain distance increased with enhanced interactions (hydrophobic interactions in particular), and this was in good agreement with the highest swelling ratio of the Naf membrane in aqueous IPA and EA solvents. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013