Updated publication reference for PubMed record(s): 30983354. The immune system is thought to be fragile in the neonate, which is susceptible to pathogens. Exosomes are a type of vehicles existing in the body fluid and participate in many biological processes, especially the immune response. Inorder to investigate the roles that exosomes may play during virus infection in the neonate, porcine epidemic diarrhea virus (PEDV), a devastating enteric virus to newborn piglets, was selected for infection. Serum exosomes were then isolated from the newborn-piglets infected or mock-infected with PEDV and followed by a label-free LC-MS/MS based comparative quantitative proteomic analysis. Among 441 proteins detected in the serum exosomes, there were lots of complement proteins. The expression level of the complement C3, C6 and CFB suffered drastic changes due to PEDV infection. After the confirmation by western-blot assay, we then investigated the function of these exosomes on PEDV infection and discovered that the exosomes from mock-infected newborn piglets restricted PEDV infection but this inhibition disappeared after exosomes were heat-inactivated, suggesting that the complement is one of the key antiviral molecules. These findings will facilitate the understanding of the antiviral response of the neonate mediated by exosomes