In this paper, we describe studies of the retention characteristics of nonpolar molecules with a novel liquid-crystalline, silica-supported, comb-shaped polymer chromatographic phase, Sil-ODA18. These results extend and amplify previous reports of the roles of enthalpic- and entropic-driven processes in the modulation of the selectivity of nonpolar and polar compounds in reversed-phase high-performance liquid chromatography (RP-HPLC). The investigations reveal that phase reorganization is the most important factor controlling selectivity enhancement with silica-supported, comb-shaped polymer phases as the temperature, T, of the system is varied. Moreover, these studies demonstrate that contributions from the stationary and the mobile phases can be independently fine-tuned to achieve enhanced selectivity via partition and/or adsorption binding processes. The relevant thermodynamic parameters, namely, the changes in enthalpy, entropy, and heat capacity for various nonpolar solutes with this comb-shaped polymeric sorbent, have also been determined using recently developed analytical procedures for the evaluation of nonlinear van't Hoff plots. These investigations into the thermodynamic properties of the comb-shaped polymeric sorbent in its ordered crystalline and noncrystalline states clearly delineate the differences in binding behavior compared to conventional types of monolayer n-alkylsilica sorbents and thus should facilitate wider application of this new class of reversed-phase sorbents in the separation sciences.