Density functional theory (DFT) calculations are used to investigate the reaction mechanism of V(3)O(8)+C(2)H(4). The reaction of V(3)O(8) with C(2)H(4) produces V(3)O(7)CH(2)+HCHO or V(3)O(7)+CH(2)OCH(2) overall barrierlessly at room temperature, whereas formation of hydrogen-transfer products V(3)O(7)+CH(3)CHO 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 (O(b))(2)V(O(t)O(t))(.) (b=bridging, t=terminal) moiety containing the oxygen radical in V(3)O(8) is the active site in the reaction with C(2)H(4). Similarities and differences between the reactivities of (O(b))(2)V(O(t)O(t))(.) in V(3)O(8) and the small VO(3) cluster [(O(t))(2)VO(t) (.)] are discussed. Moreover, the effect of the support on the reactivity of the (O(b))(2)V(O(t)O(t))(.) active site is evaluated by investigating the reactivity of the cluster VX(2)O(8), which is obtained by replacing the V atoms in the (O(b))(3)VO(t) support moieties of V(3)O(8) with X atoms (X=P, As, Sb, Nb, Ta, Si, and Ti). Support X atoms with different electronegativities influence the oxidative reactivity of the (O(b))(2)V(O(t)O(t))(.) active site through changing the net charge of the active site. These theoretical predictions of the mechanism of V(3)O(8)+C(2)H(4) 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.