Reactions with blood components are crucial for controlling the antidiabetic, anticancer, and other biological activities of V(V) and V(IV) complexes. Despite extensive studies of V(V) and V(IV) reactions with the major blood proteins (albumin and transferrin), reactions with whole blood and red blood cells (RBC) have been studied rarely. A detailed speciation study of Na3[(VO4)-O-v] (A), Ic[(V2O2)-O-IV(citr)(2)center dot 6H(2)O (B; citr = citrato(4)); [Vw0(ma)(2)] (C; ma = maltolato(-)), and (NH4)[Vv(O)(2)(dipic)] (D; dipic = pyridine-2,6-dicarbox-ylato(2)) in whole rat blood, freshly isolated rat plasma, and commercial bovine serum using X-ray absorption near-edge structure XANES) spectroscopy is reported. The latter two compounds are potential oral antidiabetic drugs, and the former two are likely to represent their typical decomposition products in gastrointestinal media. XANES spectral speciation was performed by principal component analysis and multiple linear regression techniques, and the distribution of V between RBC and plasma fractions was measured by electrothermal atomic absorption spectroscopy. Reactions of A, C, or D with whole blood (1.0 rnM V, 1-6 h at 310 K) led to accumulation of'-50% of total V in the RBC fraction (-10% in the case of B), which indicated that RBC act as V carriers to peripheral organs. The spectra of V products in RBC were independent of the initial V complex, and were best fitted by a combination of V(IV) carbohydrate (2-hydroxyacid moieties) and/or citrate (65-85%) and V(V) protein (is35%) models. The presence of RBC created a more reducing environment in the plasma fraction of whole blood compared with those in isolated plasma or serum, as shown by the differences in distribution of V(IV) and V(V) species in the reaction products of A D in these media. At physiologically relevant V concentrations (<50 tiM), this role of RBC may promote the formation of V(M)-transferrin as a major V carrier in the blood plasma. The results reported herein have broad implications for the roles of RBC in the transport and speciation of metal pro-drugs that have broad applications across medicine.