not-yet-known not-yet-known not-yet-known unknown Background: The innate immune system is activated at the onset of food protein-induced enterocolitis syndrome (FPIES) symptoms. However, the precise mechanism through which this immune response is initiated remains unclear. Objective: We aimed to investigate the proteomic profile of FPIES during symptom development through in-depth serum and saliva proteomic analyses. Methods: We enrolled 17 patients with a previous diagnosis of egg yolk FPIES who underwent an oral food challenge test (OFC) with 5 g of heated egg yolk. Six patients showed positive OFC results, whereas 11 showed negative OFC results. Serum and saliva samples were collected before OFC and 1 and 2 h after ingestion. Serum was also collected at symptom onset. We analyzed serum and saliva peptides using data-independent acquisition-mass spectrometry and compared levels to identify protein groups and pathways important in FPIES symptom development. Results: We detected 4,138 and 7,202 proteins in the serum and saliva, respectively. The OFC-positive group exhibited 609 serum proteins with more than a two-fold change in expression 2 h after OFC, including proteasome subunits and neddylation-related proteins. We identified 304 proteins associated with symptom onset, including those related to the degradation response and neutrophil extracellular trap formation. Proteins related to neutrophil activation increased both in the serum and saliva, regardless of the onset of symptoms. Conclusion: Our findings suggest that changes in protein levels, including proteasome and neddylation-related proteins, may be involved in FPIES pathogenesis and warrant further investigation to address the growing clinical burden imposed by gastrointestinal allergies.