A novel inverse CeO2/CuO catalyst for preferential oxidation of CO in H-2-rich stream (CO-PROX) has been developed on the basis of a hypothesis extracted from previous work of the group (JACS 2007, 129, 12064). Possible separation of the two competing oxidation reactions involved in the process (of CO and H-2, respectively) is the key to modulation of overall CO-PROX activity and is based on involvement of different sites as most active ones for each of the two reactions. Achievement of large size CuO particles and adequate CeO2-CuO interfacial configurations in the inverse catalyst apparently allows appreciable enhancement of the catalytic properties of this kind of system for CO-PROX, constituting an interesting alternative to classic direct configurations so far explored for this process. Reasons for such behavior are analyzed on the basis of operando-XRD, -XAFS, and -DRIFTS studies.