The binding of V(IV)O²⁺ to human serum transferrin (hTF) at the FeIII binding sites is addressed. Geometry optimization calculations were performed for the binding of V(IV)O²⁺ to the N-terminal lobe of hTF (hTFN), and indicate that in the presence of CO₃²⁻ or HCO₃ −, V(IV) is bound to five atoms in a distorted geometry. The structures of V(IV)O-hTFN species optimized at the semiempirical level were also used to calculate the ⁵¹V and ¹⁴N A tensors by density functional theory methods, and were compared with the reported experimental values. Globally, of all the calculated V(IV)O-hTF structures, the one that yields the lowest calculated heats of formation and minimum deviations from the experimental values of the ⁵¹V and ¹⁴N A tensor components is the structure that includes CO₃²⁻ as a synergistic anion. In this structure the V=O bond length is approximately 1.6 Å, and the vanadium atom is also coordinated to the phenolate oxygen atom of Tyr188 (at approximately 1.9 Å), the aspartate oxygen atom of Asp63 (at approximately 1.9 Å), the His249 Nτ atom (at approximately 2.1 Å), and a carbonate oxygen atom (at approximately 1.8 Å). The Tyr95 phenolic ocygen atom is approximately 3.3 Å from the metal center, and thus is very weakly bound to V(IV). All of these oxygen atoms are able to establish dipolar interactions with groups of the protein.