(E)-4-Hydroxy-2-nonenal (HNE) is a highly cytotoxic aldehyde generated during peroxidation of lipids, which induces modification and aggregation of low-density lipoproteins and has been found to elicit covalent cross-linking of proteins. Carnosine was previously shown to trap HNE. Results presented here provide evidence that by trapping HNE in stable covalent adducts, carnosine can inhibit HNE-induced protein cross-linking. This trapping effect may be augmented by carnosine-chelating trace transition metal ions that promote oxidative HNE-induced cross-linking. Adducts formed in the reaction of HNE with carnosine have been isolated and structurally characterized. The main carnosine-HNE adduct is shown to be a 13-member cyclic adduct formed through initial Schiff base formation followed by conjugate addition of the imidazole group.