It is known that a methanol/water mixture has a quaternary organization consisting of free water W, free methanol M, and two types of methanol/water clusters. A 1:1 methanol/water cluster has been observed at a high methanol concentration, and a 5:1 cluster has been observed at a low methanol concentration. In the water fraction range used in this paper, 0.2-0.7, the number of MW(5) clusters was always inferior to the number of MW clusters. When a weak polar solute is introduced into such a mixture, it is preferentially solvated by free methanol and the MW water clusters. Using this mixture as the mobile phase, a novel mathematical theory is presented to describe, in this water fraction range, the variations of the retention factor k' of alkyl benzoate esters and benzodiazepines in reversed-phase liquid chromatography. Excellent predictions of k' versus free methanol and methanol/water fractions were obtained. For the first time, using this model, enthalpy, entropy, and the Gibbs free energy of the two solute solvation processes were evaluated. Enthalpy-entropy compensation revealed that the main parameters determining retention in the range of the water fraction (0.2-0.7) increased as follows: free methanol ↔ solute solvation > methanol/water cluster ↔ solute solvation > RP18 stationary phase ↔ solute interaction. These results agree well with values obtained when ACN was used instead of methanol.