In this work, based on first principles density functional theory, we have investigated the interaction of SO3 molecule on three different substrates; (i) clean Al2O3 surface (0001) (ii) an isolated Ag-6 cluster and (iii) Ag-6 clusters deposited on the Al2O3 surface. All calculations were carried out using the plane wave based pseudopotential method under the framework of density functional theory. For the clean Al2O3 surface, the SO3 molecule was adsorbed in parallel orientation on the surface resulting in an elongation of the S-O bond from 1.44 to 1.52 angstrom with interaction energy of 1.67 eV. In contrast, the interaction of SO3 with Ag-6 was found to be weak with 0.4 eV interaction energy and 1.47 angstrom as the largest S-O bond length. Remarkably, when SO3 molecule interacted with Ag-6 cluster deposited on the Al2O3 support, the binding was found to be higher than both Al2O3 and Ag-6 clusters in their isolated state. In particular, upon adsorption of SO3 on Ag-6/@Al2O3, the S-O bond length was found to increases from 1.44 to 1.64 angstrom and the interaction energy was estimated to be 2.00 eV. As the bond elongation bears the signature of bond weakening, a comparison of the above three results clearly suggests that the dissociation barrier of S-O bond on the Ag-6@Al2O3 support will be significantly lower than that on the isolated Ag-6 or Al2O3 surface. The nature of chemical interaction of SO3 on these three systems has been discussed based on the electronic density of states analysis. Copyright (C) 2011, Hydrogen Energy Publications, LLC. Published by Elsevier Ltd. All rights reserved.