Using density functional theory periodic calculations, we investigate the effects of two relevant supports for industrial hydrodesulfurization catalysts, anatase (titania) and γ-alumina, on the thermodynamic stability Of Mo6Sn (n = 10 to 24) clusters representing the MoS2 active phase. Under HDS conditions, anatase surfaces stabilize more sulfur-deficient small clusters than alumina surfaces. Because of an epitaxy relationship, the anatase surfaces also enhance tilted and perpendicular cluster orientations. For large cluster sizes, we establish a model extrapolating the energetic properties obtained on supported Mo6Sn clusters that reveals how the nature of the chemical interaction of the MoS2 single layer is modified. A concept based on competing "ligand effects" between the support and the gas phase on the active phase is proposed to explain our results. These new insights are in line with the higher intrinsic HDS activity reported for the anatase-supported MoS2 catalyst. © 2005 Elsevier Inc. All rights reserved.