Abstract: Methods and reagents to obtaining a sample enriched in peptides comprising the third complementarity-determining region of the heavy chain (CDRH3) of immunoglobulins, such as IgGs, are described. These methods are based on the use of targeted protease digestion of immunoglobulins and affinity purification of CDRH3 peptides using specific antibodies. Such methods and reagents are useful for analyzing the immunoglobulin repertoire.