The insulin-mimetic activity of the VO 2þ complexes are much related to its chemical speciation in the blood serum. Low molecular mass ligands must have an important role in the mechanism of the VO 2þ biological activity affecting directly its absorption efficacy. In the present work, the chemical speciation of vanadyl (VO 2þ ) with malonate, maltolate, oxalate and picolinate ligands has been investigated by means of DFT/PCM calculations. Metal/Ligand 1:1 and 1:2 complexes have been calculated. All tautomers, conformations and the presence of water molecules acting as ligand fulfilling the coordination sphere of the metal center have been studied. The results showed that the 1:1 species prefer to have square pyramidal structure with two water molecules in the equatorial axis. The 1:2 species prefer the hexacoordinated structure with one water molecule in the available coordination site in the cis position with respect to the oxo group. The 6-membered ring malonate complex prefers to keep the square pyramidal structure without water molecule in the coordination sphere. The Gibbs free reaction energy for the formation of the 1:2 complexes from the interaction of the 1:1 complexes and the ligand was estimated. The error of the estimated values compared to the experimental data is not larger than 5 kcal mol À1 at the PBE/TZVP level of theory