The gas-phase reactivity of the vanadium hydroxides [VO(2)(OH)(2)](-) and [V(2)O(5)(OH)](-) toward methanol was examined using a combination of ion-molecule reactions (IMRs) and collision-induced dissociation (CID) in a quadrupole ion trap mass spectrometer. Isotope-labeling experiments with CD(3)OH, (13)CH(3)OH, and CH(3)(18)OH were used to confirm the stoichiometry of ions and the observed sequence of reactions. The experimental data were interpreted with the aid of density functional theory calculations, carried out at the B3LYP/SDD6-311++G** level of theory. While [VO(2)(OH)(2)](-) is unreactive, [V(2)O(5)(OH)](-) undergoes a metathesis reaction to yield [V(2)O(5)(OCH(3))](-). The DFT calculations reveal that the metathesis reaction of methanol with [VO(2)(OH)(2)](-) suffers from a barrier of +0.52 eV (relative to separated reactants) but that the reaction of [V(2)O(5)(OH)](-) with methanol readily proceeds via addition/elimination reactions with both transition states being below the energy of the separated reactants. CID of [V(2)O(5)(OCH(3))](-) (m/z 213) yields three ions arising from activation of the methoxo ligand: [V(2), O(6), C, H](-) (m/z 211); [V(2), O(5), H](-) (m/z 183); and [V(2), O(4), H](-) (m/z 167). Additional experiments and DFT calculations suggest that these ions arise from losses of H(2), formaldehyde and the sequential losses of H(2) and CO(2), respectively. The use of an (18)O-labeled methoxo ligand in [V(2)O(5)((18)OCH(3))](-) (m/z 215) showed the competing losses of H(2)C(16)O and H(2)C(18)O and [H(2) and C(16)O(18)O] and [H(2) and C(16)O(2)], highlighting that (16)O/(18)O exchange between the methoxo ligand and the vanadium oxide occurs prior to the subsequent fragmentation of the ligand. DFT calculations reveal that a key step involves hydrogen atom transfer from the methoxo ligand to the oxo ligand of the same vanadium center, producing the intermediate [V(2)O(4)(OH)(OCH(2))](-) containing a ketyl radical ligand and a hydroxo ligand. This intermediate can either undergo CH(2)O loss, or the ketyl radical can couple with an oxo ligand of the adjacent vanadium center, producing [V(2)O(3)(μ(2)-O(2)CH(2))](-), which is a key intermediate in the (16)O/(18)O scrambling and in the H(2) loss channel.