Heating food proteins promotes a reaction between proteins and sugars called the Maillard reaction (MR). Maillard reaction products (MRPs) have been linked to increased immunogenicity of proteins through interaction with receptors for advanced glycation end products (RAGE). Here, we aimed to characterize the functional properties of whey protein hydrolysates (WPHs) and its' fractions. A partial WPH1 and an extensive WPH2 were size fractionated. The MRPs were detected with anti-Nε-carboxymethyllysine (CML) antibody and binding to RAGE was measured using inhibition ELISA. Induction of pro-inflammatory cytokines was determined in THP-1-derived macrophages, and the capacity to induce degranulation of basophils was assessed using FcεRI+ RBL cells. The partial WPH1, but not WPH2, contained high MW fractions (aggregates >
100 kDa) which bound to RAGE and induced the production of IL-6, IL1-β, and IL-8 in THP-1 macrophages. The aggregates of WPH1, but not the smaller fractions, induced the degranulation of FcεRI+ RBL cells. The presence of high MW glycated aggregates in partial WPHs leads to increased binding to RAGE, production of pro-inflammatory cytokines, and basophil degranulation in the presence of whey-specific IgE. This implies that the safety and functionality of partially hydrolyzed formulas should not be generalized due to their composition and potential immunogenicity of glycated aggregates.