Advanced glycation of collagens contributes to development of micro- and macrovascular complications in diabetes. Since flavonoids are potent natural antioxidants, it was interesting to examine their effect on the formation of a cross-linking advanced glycation endproduct, pentosidine, in collagen incubated with glucose. Monomeric flavonoids (25 and 250 microM) markedly reduced pentosidine/hydroxyproline values in a concentration- and structure-dependent manner. Procyanidin oligomers from grape seed were more active than pine bark procyanidin oligomers. Oligomers are known to be cleaved into monomers in the gastric milieu and monomeric flavonoids to be absorbed and recovered at micromolar concentrations (with a long plasmatic half-life) in extracellular fluids, in contact with collagens. In conclusion, flavonoids are very potent inhibitors of pentosidine formation in collagens, active at micromolar concentrations; these concentrations might be achieved in plasma of diabetic patients after oral intake of flavonoids.