A novel inverse CeO2/CuO catalyst for preferential oxidation of CO in H2-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 H2, 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.