Reactions of niobium and tantalum oxide cluster cations (MxOy+) and anions (MxOy-) with n-butane (C4H10) are reported. The major reaction channels observed during the reaction of certain stoichiometric niobium and tantalum oxide cluster cations include association of n-butane (MxOyC4H10+), C-C activation (MxOyC2H4+), loss of an oxygen atom (MxOy-1+), and dehydration (MxOy-1C4H8+). Reactions of C4H10 with oxygen-rich clusters are also reported herein and the major reaction channel of most of these oxygen-rich clusters involves a replacement reaction, where C4H10 replaces an oxygen molecule. In addition, reactions of niobium and tantalum oxide anions (MxOy-) with n-butane were also examined and it was established that the metal oxide cluster anions are unreactive toward this saturated hydrocarbon. The present study establishes the importance of the charge center, composition, size, and degree of coordinative saturation of the cluster on the reactivity with n-butane.