We aimed to clarify the pathogenesis of FPIES symptom development based on the serum and saliva proteomic profiles before symptom onset. We observed a transient increase in serum proteasome- and neddylation-related protein levels before the onset of FPIES symptoms, possibly triggering the activation of various innate immune cell types at symptom onset. Regardless of the onset of symptoms, high expression of proteins related to neutrophil activation was found in the serum and saliva before symptom onset, suggesting that initial neutrophil activation may not be necessary to initiate FPIES symptom development. However, it might be prolonged and worsen the symptoms when they occur.