A spatial configuration of the inclusion complex formed between -cyclodextrin and piroxicam has been proposed based on the ONIOM2 [HF/3.21G * :B3LYP/6.31G(d)] calculation. In the favorable configuration (namely P -orientation) the pyridine ring is totally embedded in the cyclodextrin cavity while the aromatic ring remains outside the cavity. This configuration is more favorable of 23.43 kcal/mol, comparing to the configuration in which the pyridine ring is localized outside the cavity (namely B-orientation). In order to take solvent effect into account, DFT (B3LYP/6-31G(d)) calculations using Onsager and two polarizable continuum models, CPCM and IEFPCM were carried out. The Onsager model, CPCM and IEFPCM gives P -orientation more favorable respectively of 25.71 8.26 and 8.46 kcal/mol. The geometry of the energy minima (P -orientation) leads to the formation of eight intermolecular hydrogen bonds between piroxicam and CD: Three conventional H-bonds (X H· · · O) and five weak H-bonds (C H· · · O). These interactions were investigated by Natural Bond Orbital (NBO) approach.