The present study investigated the solubilization of rofecoxib in aqueous solution using mannitol, poly(vinylpyrrolidone) K30, urea, poly(ethylene glycol) 4000, and poly(ethylene glycol) 6000 at (298.15, 303.15, and 308.15) K. The analysis of rofecoxib is carried out by high-performance liquid chromatography (HPLC). The aqueous solubility of rofecoxib could be enhanced by the addition of increasing mass fraction of all of the hydrophilic carriers tested except mannitol as well as by increasing the temperature of the dissolution medium. Among the hydrophilic carriers studied, urea exhibited a higher solubilization potential than the other carriers. Calculated Gibbs free energy values were all negative for all of the hydrophilic carriers + water mixtures at (298.15, 303.15, and 308.15) K, indicating the spontaneous nature of rofecoxib solubilization. In the case of urea + water mixtures, the Delta(tr)G degrees values decreased to a greater extent than those for the other carriers (mannitol, poly(vinylpyrrolidone) K30, poly(ethylene glycol) 4000, and poly(ethylene glycol) 6000) + water mixtures, indicating that the reaction conditions were more favorable in urea + water mixtures than in other carriers + water mixtures.