Oxygenated aromatic compounds (OACs) are used for the synthesis of a variety of commercial products. Lignin from wood and other plant products are potential sources of OACs, but it is difficult to separate the mixtures of OACs found in digests of these raw materials. One promising separation approach involves the use of selective adsorption resins, such as the acrylic ester sorbent XAD-7. It has been shown previously that this sorbent binds the para isomer of one OAC, methoxyphenol, more favorably that the ortho isomer when hexane is used as the solvent. The present study uses a combination of molecular modeling and experiment to elucidate the mechanism of this selectivity. The calculations yield good agreement with experimental binding affinities and indicate that hydrogen bonding is the dominant mode of adsorption of para-methoxyphenol onto XAD-7 from hexane. In contrast, ortho-methoxyphenol appears to form an intramolecular hydrogen bond that weakens the intermolecular hydrogen bond to the sorbent. As a consequence, ortho-methoxyphenol binds less strongly, and its association is dominated by van der Waals interactions and three-centered hydrogen bonds. This result is supported by quantum mechanical calculations and infrared spectroscopic experiments. It is also found that when water is the solvent, hydrogen bonding becomes an insignificant adsorption mechanism, and both molecules bind to the resin via nonpolar interactions. This explains the loss of selectivity that is observed in both experiment and calculation.