The present Letter reports results from a comprehensive theoretical analysis of the inclusion process involving the tetracycline (TC) by beta and gamma-cyclodextrin (CD). Structure and stabilization energies were calculated, both in gas phase and aqueous solution, using a sequential methodology based on semiempirical and density functional theory (DFT) calculations. By the results, a qualitative structure-property relationship could be established with two main structural features being relevant for inclusion complex stabilization: (i) the depth of inclusion, which favors the hydrophobic contact inside the cavity of CDs and (ii) the hydrogen bonds established between guest and host molecules. (C) 2015 Elsevier B.V. All rights reserved.