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Background: The human milk proteome comprises a vast number of proteins with immunomodulatory functions, but it is not clear how this relates to allergy of the mother or allergy development in the breastfed infant. This study aimed to explore the relation between the human milk proteome and allergy of both mother and child., Methods: Proteins were analyzed in milk samples from a subset of 300 mother-child dyads from the Canadian CHILD Cohort Study, selected based on maternal and child allergy phenotypes. For this selection, the definition of "allergy" included food allergy, eczema, allergic rhinitis, and asthma. Proteins were analyzed with non-targeted shotgun proteomics using filter-aided sample preparation (FASP) and nanoLC-Orbitrap-MS/MS. Protein abundances, based on label-free quantification, were compared using multiple statistical approaches, including univariate, multivariate, and network analyses., Results: Using univariate analysis, we observed a trend that milk for infants who develop an allergy by 3 years of age contains higher abundances of immunoglobulin chains, irrespective of the allergy status of the mother. This observation suggests a difference in the milk's immunological potential, which might be related to the development of the infant's immune system. Furthermore, network analysis showed overall increased connectivity of proteins in the milk of allergic mothers and milk for infants who ultimately develop an allergy. This difference in connectivity was especially noted for proteins involved in the protein translation machinery and may be due to the physiological status of the mother, which is reflected in the interconnectedness of proteins in her milk. In addition, it was shown that network analysis complements the other methods for data analysis by revealing complex associations between the milk proteome and mother-child allergy status., Conclusion: Together, these findings give new insights into how the human milk proteome, through differences in the abundance of individual proteins and protein-protein associations, relates to the allergy status of mother and child. In addition, these results inspire new research directions into the complex interplay of the mother-milk-infant triad and allergy., Competing Interests: MA holds a Tier 2 Canada Research Chair in the Developmental Origins of Chronic Disease at the University of Manitoba and is a Fellow in the Canadian Institutes for Advanced Research (CIFAR) Humans and the Microbiome Program. She receives research funding from the Canadian Institutes of Health Research, Research Manitoba, the Canada Foundation for Innovation, the Bill and Melinda Gates Foundation, the Manitoba Children’s Hospital Foundation, Prolacta Biosciences, Mitacs, CIFAR, the Garfield Weston Foundation, Health Data Research UK, and Canadian COVID Immunity Task Force. She regularly speaks at conferences and workshops on infant nutrition, some sponsored by Prolacta Biosciences, and has spoken at a conference sponsored by AstraZeneca. She has contributed without remuneration to online courses on breast milk and the infant microbiome produced by Microbiome Courses. She serves in a volunteer capacity for the International Society for Research on Human Milk and Lactation and as a member of the US Canada Joint Human Milk Initiative. She has consulted for DSM Nutritional Products and serves on the Malaika Vx Scientific Advisory Board. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dekker, Azad, Boeren, Mandhane, Moraes, Simons, Subbarao, Turvey, Saccenti and Hettinga.)