The interaction of H2S with the Cu/CeO2 system is investigated using the first-principles method. It is found that the formation energy of surface oxygen vacancies is lower than that of interface oxygen vacancies and the spillover of an oxygen ion from ceria to Cu strip is an exothermic process, suggesting that the oxygen ions in the substrate are extremely active. The dissociation of H2S molecule forms atomic S, which is absorbed preferentially at the Cu strip on both unreduced and reduced Cu/CeO2(110), instead of interacting with the ceria and diffusing into the ceria bulk, alleviating the deactivation of the ceria. On the other hand, the sulfur atom at the Cu strip could be removed by forming SO2 at suitable partial pressure of water as suggested by our thermodynamics prediction. Therefore the accumulation of sulfur at the Cu strip and the sulfur poisoning to the Cu/CeO2 system can be avoided. Copyright (C) 2013, Hydrogen Energy Publications, LLC. Published by Elsevier Ltd. All rights reserved.