The main goal of the present density functional theory calculations is a comparative study of NO, O2, NO−2, and H2O binding to different forms of cob(II)alamins and cob(III)alamins.The comparison of binding energies of small ligands enables one to draw conclusions regarding the stability of the studied derivatives of cobalamins as well as to define the preferred form of cobalamin for each ligand. Ligands such as NO and O2 favor cob(II)alamins, while H2O and NO−2 cob(III)alamins. The obtained results are confronted with available experimental data. Finally, our findings allow one to divide the studied small ligands into two groups: NO and O2 for which the coordination to cobalamins significantly weakens their internal bonds, and NO−2 and H2O for which the effect is not observed.