The experimental solubility behavior of 6-methyl-2-thiouracil in co-solvent mixtures of (methanol, N-methyl-2-pyrrolidone, N, N-dimethyl formamide or dimethylsulfoxide) + water were measured by the isothermal dissolution equilibrium method at elevated temperatures between 278.15 K and 323.15 K under about 101.2 kPa. The solubility of 6-methyl-2-thiouracil increased positively with increasing temperature and molar fraction of organic solvents in each binary system. The minimum solubility was observed in neat water. At the same temperature and mass fraction of the organic solvent, the solubility of 6-methyl-2-thiouracil was greater in (dimethylsulfoxide + water) than in the other three mixed solvents. The solid phase 6-methyl-2-thiouracil was tested by X-ray power diffraction, which showed that no polymorphic transformation, solvate formation or crystal transition during entire experiments conclusively. The measured solubility data was correlated with the Jouyban-Acree model, Van't Hoff-Jouyban-Acree model and Apelblat-Jouyban-Acree model. The calculated data was in good agreement with the experimental values within the temperature range studied and the maximum of relative average deviation and root-mean-square deviation were 3.64 x 10(-2) and 5.68 x 10(-4), respectively. The dissolution process of 6-methyl-2-thiouracil in the four co-solvent mixtures was endothermic. The solvent effect analysis indicates that the hydrogen bond acceptor capacity and dipolarity-polarizability of solvent control mainly the variation in the solubility. Furthermore, the preferential solvation parameters were derived from their thermodynamic solution properties by using the inverse Kirkwood-Buff integrals. For the four co-solvent mixtures with intermediate composition and co-solvent-rich mixtures, 6-methyl-2-thiouracil was preferentially solvated by co-solvent. It could act mainly as a Lewis acid interacting with proton-acceptor functional groups of the co-solvents. (C) 2018 Elsevier Ltd.