The reactions of cerium-vanadium cluster cations CexVyOz + with CH4 are investigated by time-of-flight mass spectrometry and density functional theory calculations. (CeO2)(m)(V2O5)(n)+ clusters (m = 1,2, n = 1-5; m = 3, n = 1-4) with dimensions up to nanosize can abstract one hydrogen atom from CH4. The theoretical study indicates that there are two types of active species in (CeO2)(m)(V2O5)(n) +, V[(O-t)(2)](center dot) and [(O-b)(2)CeOt](center dot) (O-t and O-b represent terminal and bridging oxygen atoms, respectively); the former is less reactive than the latter. The experimentally observed size-dependent reactivities can be rationalized by considering the different active species and mechanisms. Interestingly, the reactivity of the (CeO2)(m)(V2O5)(n) + clusters falls between those of (CeO2)(2-4) + and (V2O5)(1-5) + in terms of C-H bond activation, thus the nature of the active species and the cluster reactivity can be effectively tuned by doping.