Specific interactions between molecules, including those produced by a given solute, and the surrounding solvent are essential to drive molecular recognition processes. A simple molecule such as benzene is capable of recognizing and differentiating among very similar entities, such as methyl 2,3,4,6-tetra-O-methyl-α-d-galactopyranoside (α-Me5Gal), methyl 2,3,4,6-tetra-O-methyl-β-d-galactopyranoside (β-Me5Gal), 1,2,3,4,6-penta-O-acetyl-β-d-galactopyranose (β-Ac5Gal), and methyl 2,3,4,6-tetra-O-methyl-α-d-mannopyranoside (α-Me5Man). In order to determine if these complexes are formed, the interaction energy between benzene and the different carbohydrates was determined, using Calvet microcalorimetry, as the enthalpy of solvation. These enthalpy values were −89.0 ± 2.0, −88.7 ± 5.5, −132.5 ± 6.2, and −78.8 ± 3.9 kJ mol−1 for the four complexes, respectively. Characterization of the different complexes was completed by establishing the molecular region where the interaction takes place using NMR. It was determined that β-Me5Gal is stabilized by the CH/π interaction produced by the nonpolar region of the carbohydrate on the α face. In contrast, α-Me5Man is not specifically solvated by benzene and does not present any stacking interaction. Although α-Me5Gal has a geometry similar to that of its epimer, the obtained NMR data seem to indicate that the axial methoxy group at the anomeric position increases the distance of the benzene molecules from the pyranose ring. Substitution of the methoxy groups by acetate moieties, as in β-Ac5Gal, precludes the approach of benzene to produce the CH/π interaction. In fact, the elevated stabilization energy of β-Ac5Gal is probably due to the interaction between benzene and the methyl groups of the acetyls. Therefore, methoxy and acetyl substituents have different effects on the protons of the pyranose ring.