hydrophobic substances in water. Moreover, water, when present in small quantities, has also been shown to increase the solubility of hydrophobic substances in Cyrene. In spite of large practical importance, the understanding of the solvation ability of water/Cyrene mixtures is hampered by a lack of fundamental knowledge of their solvation mechanisms, which is further complicated by a chemical equilibrium established between the ketone form of Cyrene and water, yielding the diol form of Cyrene. In this work, the conductor-like screening model for real solvents (COSMO-RS) is used to rationalize the cosolvency effect of water on Cyrene. It is shown here that COSMO-RS can accurately predict the solubility of hydrophobic substances in water/Cyrene mixtures in the entire composition range from pure water to pure Cyrene. The predictions of the model show that the ketone form of Cyrene controls its hydrotropic ability, supporting the concept of cooperative hydrotropy. Using COSMO-RS to assess molecular contact probability, it is also shown that water, when added in small quantities to Cyrene, acts as a cosolvent by preferentially interacting with the solute as a hydrogen bond acceptor, effectively doubling the hydrogen-bond donning ability of the solute and, thus, maximizing the interactions with Cyrene. In turn, this leads to a solubility increase of hydrophobic substances in wet Cyrene.