Oxidative modifications to the side chains of sulfur-containing amino acids often limit the number of product ions formed during collision-induced dissociation (CID) and thus make it difficult to obtain sequence information for oxidized peptides. In this work, we demonstrate that electron-transfer dissociation (ETD) can be used to improve the sequence information obtained from peptides with oxidized cysteine and methionine residues. In contrast to CID, ETD is found to be much less sensitive to the side-chain chemistry, enabling extensive sequence information to be obtained in cases where CID fails to provide this information. These results indicate that ETD is a valuable technique for studying oxidatively modified peptides and proteins. In addition, we report a unique and very abundant product ion that is formed in the CID spectra of peptides having N-terminal cysteine sulfinic acid residues. The mechanism for this unique dissociation pathway involves a six-membered cyclic intermediate and leads to the facile loss of NH 3 and SO 2 , which corresponds to a mass loss of 81 Da. While the facile nature of this dissociation pathway limits the sequence information present in CID spectra of peptides with N-terminal cysteine sulfinic acid residues, extensive sequence information for these peptides can be obtained with ETD. M ass spectrometry (MS) is widely used for sequencing and identifying amino acid modifications in peptides and proteins. Identifying modifications to proteins is important for a variety of reasons. Post-translational modifications (PTMs) of proteins are necessary for a wide range of cellular functions such as protein trafficking, protein-protein interactions, and transcription. Identifying and pinpointing these modification sites are important for more deeply understanding protein function, both normal and abnormal. In this context, PTMs such as phosphorylation, acetylation, glycosylation, sulfonation, and methylation are important to characterize. Oxidation is another important protein modification that is typically associated with oxidative stress [1-4], but recent work has also shown that protein oxidation can play a regulatory role as well [5]. Furthermore, an increasing number of techniques make use of oxidative labeling to study protein structure. These methods use radicals (e.g., · OH) to modify solvent-exposed [6 -9] or metal-bound amino acids [10 -17], and MS n to identify oxidatively modified residues, typically in conjunction with proteolytic digestion.Very often side-chain modifications to peptides can make sequencing by collision-induced dissociation (CID) difficult. Perhaps the most well known example is the effect of phosphorylation on peptide ion dissociation. The CID spectra of phosphorylated peptides are commonly dominated by a neutral loss of H 3 PO 4 , often with little other sequence information present. Similarly, side-chain oxidation can dramatically affect peptide dissociation patterns and limit sequence information that is available by CID. For example, oxidation of cysteine ...