Density functional theory (DFT) calculations are used to investigate the reaction mechanism of V3O8+C2H4. The reaction of V3O8 with C2H4 produces V3O7CH2+HCHO or V3O7+CH2OCH2 overall barrierlessly at room temperature, whereas formation of hydrogen-transfer products V3O7+CH3CHO is subject to a tiny overall free energy barrier (0.03 eV), although the formation of the last-named pair of products is thermodynamically more favorable than that of the first two. These DFT results are in agreement with recent experimental observations. The (Ob)2V(OtOt). (b=bridging, t=terminal) moiety containing the oxygen radical in V3O8 is the active site in the reaction with C2H4. Similarities and differences between the reactivities of (Ob)2V(OtOt). in V3O8 and the small VO3 cluster [(Ot)2VOt.] are discussed. Moreover, the effect of the support on the reactivity of the (Ob)2V(OtOt). active site is evaluated by investigating the reactivity of the cluster VX2O8, which is obtained by replacing the V atoms in the (Ob)3VOt support moieties of V3O8 with X atoms (X=P, As, Sb, Nb, Ta, Si, and Ti). Support X atoms with different electronegativities influence the oxidative reactivity of the (Ob)2V(OtOt). active site through changing the net charge of the active site. These theoretical predictions of the mechanism of V3O8+C2H4 and the effect of the support on the active site may be helpful for understanding the reactivity and selectivity of reactive O. species over condensed-phase catalysts.