Density functional theory has been applied to the investigation of the reductive cleavage mechanism of methylcobalamin (MeCbl). In the reductive cleavage of MeCbl, the Co-C bond is cleaved homolytically, and formation of the anion radical ([MeCbl](center dot-)) reduces the dissociation energy by similar to 50%. Such dissociation energy lowering in [MeCbl](center dot-) arises from the involvement of two electronic states: the initial state, which is formed upon electron addition, has dominant pi*(corrin) character, but when the Co-C bond is stretched the unpaired electron moves to the sigma*(Co-C) state, and the final cleavage involves the three-electron (sigma)(2)(sigma*)(1) bond. The pi*(corrin)-sigma*(Co-C) states crossing does not take place at the equilibrium geometry of [MeCbl](center dot-) but only when the Co-C bond is stretched to 2.3 A. In contrast to the neutral cofactor, the most energetically efficient cleavage of the Co-C bond is from the base-off form. The analysis of thermodynamic and kinetic data provides a rationale as to why Co-C cleavage in reduced form requires prior departure of the axial base. Finally, the possible connection of present work to B-12 enzymatic catalysis and the involvement of anion-radical-like [MeCbl](center dot-) species in relevant methyl transfer reactions is discussed.