Mole fraction solubilities of tadalafil (3) in aqueous mixtures of Transcutol® and PEG 400 at temperatures from 298.15 to 333.15 K were analysed following Hildebrand solubility parameters. Cosolvency models for representing tadalafil solubility at various temperatures were also provided for correlation/prediction purposes. Apparent thermodynamic quantities for tadalafil dissolution processes were calculated based on van't Hoff and Gibbs equations. Non-linear enthalpy–entropy compensation was observed for tadalafil transfer from more polar to less polar solvent systems. Preferential solvation parameters of tadalafil at 298.15 and 313.15 K were determined by means of the inverse Kirkwood-Buff integrals (IKBI). Tadalafil is preferentially solvated by water in water-rich mixtures of Transcutol® but preferentially solvated by Transcutol® in mixtures of 0.12 < x1 < 1.00. In the former case, this result could be due to hydrophobic hydration around the non-polar moieties of tadalafil. Otherwise, tadalafil is preferentially solvated by PEG 400 in all the aqueous mixtures.