Guest–host interactions of ibuprofen tromethamine salt (Ibu.T) with native and modified cyclodextrins (CyDs) have been investigated using several techniques, namely phase solubility diagrams (PSDs), proton nuclear magnetic resonance ( 1 H NMR), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), X-ray powder diffractometry (XRPD), scanning-electron microscopy (SEM) and molecular mechanics (MM). From the analysis of PSD data (A L -type) it is concluded that the anionic tromethamine salt of ibuprofen (pK a =4.55) forms 1:1 soluble complexes with all CyDs investigated in buffered water at pH 7.0, while the neutral form of Ibu forms an insoluble complex with β-CyD (B S -type) in buffered water at pH 2.0. Ibu.T has a lower tendency to complex with β-CyD (K 11 =58M −1 at pH 7.0) compared with the neutral Ibu (K 11 =4200M −1 ) in water. Complex formation of Ibu.T with β-CyD (ΔG°=−20.4kJ/mol) is enthalpy driven (ΔH°=−22.9kJ/mol) and is accompanied by a small unfavorable entropy (ΔS°=−8.4J/molK) change. 1 H NMR studies and MM computations revealed that, on complexation, the hydrophobic central benzene ring of Ibu.T and part of the isobutyl group reside within the β-CyD cavity leaving the peripheral groups (carboxylate, tromethamine and methyl groups) located near the hydroxyl group networks at either rim of β-CyD. PSD, 1 H NMR, DSC, FT-IR, XRPD, SEM and MM studies confirmed the formation of Ibu.T/β-CyD inclusion complex in solution and the solid state.