To clarify the relationship between the type of the oxide support and the activity of the gold-doped oxide clusters toward H-2 oxidation, a suitable closed-shell system AuV2O5+ is chosen to have a comparative study with AuCe2O4+, the first closed-shell cluster that is reactive toward H-2 oxidation. The reaction of AuV2O5+ with H-2 was characterized by mass spectrometry and density functional theory calculations. The AuV2O5+ cluster is reactive toward H-2 leading to the major product of V2O5H2+ (+ Au), whereas the product of AuV2O4+ (+ H2O) is completely absent in the experiment. This is in sharp contrast with the similar reaction system of AuCe2O4+ with H-2, in which the formation of H2O was experimentally evidenced. Theoretical calculations revealed that the distinct reaction behaviors between AuV2O5+ and AuCe2O4+ can be attributed to the gold-metal bond strength, which plays an important role in anchoring the gold atom. The weaker AuV bond promotes the evaporation of Au, which has a negative effect on the total oxidation of H-2 to H2O. This comparative study provides molecular-level mechanisms to understand the important roles of the goldmetal bond in the oxidation of hydrogen molecule over metal oxide supports.