Abstract In this study, the interactions in aqueous binary and ternary systems containing polyethylene glycol (6000) and erythromycin at different temperatures were investigated to utilize this information in the aqueous two-phase method for different purposes, including separation and purification. Through experimental methods, density, sound velocity, and viscosity at 293.15, 303.15, and 313.15 K were measured in aqueous solutions, including erythromycin and polyethylene glycol. From the experimental density data, apparent molar volume (ϕ V), limiting apparent molar volume (ϕ V 0) and transfer molar volume ( ∆ t r ϕ V 0 ) ${{\increment}}_{\mathrm{t}\mathrm{r}}{\phi }_{\mathrm{V}}^{0})$ have been calculated. Also, the experimental sound velocity data determined apparent molar isentropic compressibility (ϕ k), limiting apparent molar isentropic compressibility (ϕ k 0) and transfer isentropic compressibility ( ∆ tr ϕ k 0 ) ${{\increment}}_{\mathrm{tr}}{\phi }_{\mathrm{k}}^{0})$ values of polyethylene glycol (6000) from water to erythromycin solutions. Furthermore, experimental viscosity data and the Jones–Dole equation determined viscosity β ′-coefficient and transfer viscosity β ′-coefficient ( ∆ t r β ′ ) ${{\increment}}_{\mathrm{t}\mathrm{r}}{\beta }^{\prime })$ values. The obtained results investigated the polymer effect as kosmotropic or chaotropic on erythromycin drug and the interaction between polyethylene glycol and erythromycin (solute-solute interactions). The results show that the interaction between drug and polymer is more desirable in the high-concentration polymer. Finally, results indicate that polyethylene glycol (6000) has played a kosmotropic role in aqueous solutions of erythromycin.