Specific IgE and IgG4 have been reported to play key roles in the context of IgE-mediated cow's milk allergy (CMA), but the persistence of their epitopes in milk hydrolysates has not been evaluated. Using sera from 32 CMA patients, 6 CMA patients treated by epicutaneous therapy (CM-treated), and 4 CM-tolerant peanut allergic patients, we analyzed the IgE and IgG4 binding capacities related to major milk allergens in processed milk. Different proteases (plasmin, chymosin, alpha-chymotrypsin, or pepsin) were used progressively and selectively to hydrolyze beta-lactoglobulin (beta-LG) and casein (CN) in milk. We then showed that proteases differentially affect IgE or IgG4 immunoreactivities of CN and beta-LG and also that we could not relate IgE and/or IgG4 levels or specificities to milk hydrolysates to the clinical status of the patients.