Introduction: Early life is characterized by heightened susceptibility to infections and is recognized as a major determinant of the immune system development and the overall health for the entire human lifespan. However, our knowledge of the development of the neonatal immune system is incomplete, limiting the development of novel preventative and therapeutic strategies, especially in newborns. To gain insight into the early immune system development and plasma proteome ontogeny, the Expanded Program on Immunization Consortium (EPIC) led by Professor Ofer Levy MD at Boston Children’s Hospital, Harvard Medical School and Tobias R. Kollmann Telethon Kids Institute, Australia as part of the Human Immunological Project Consortium (HIPC), established two independent cohorts of plasma from healthy newborns born by vaginal delivery during the first week of life. Methods: Blood samples were collected from 30 newborns in The Gambia (Medical Research Council Unit, The Gambia) at the day of birth (day of life, DOL 0) and at one of the follow-up visits on DOL1, DOL3, or DOL7. A similar validation cohort was collected in Papua New Guinea (PNG) (Institute for Medical Research, Papua New Guinea, Australasian) from 19 newborns. The plasma proteome was characterized by LC-MS on a Q Exactive using the proven and published plasma proteomics platform developed in the Steen Laboratory, led by Dr Hanno Steen, Director of Proteomics at Boston Children’s Hospital, Harvard Medical School, employing only microliter of plasma prepared in a 96-well plate format. The data was analyzed with MaxQuant. Results: We characterized 385 blood-plasma proteins. Utilizing the paired study design, we identified consistent changes related to ontogeny and cellular growth pathways in the blood-plasma proteome. Conclusion: This dataset allows for studying the early ontogeny of the plasma proteome, and in extension the early immune system development, in two independent healthy cohorts. Characterization of the plasma proteome may provide novel insight into new approaches to prevent, detect, and treat infectious diseases. Acknowledgements: We would like to thank all the participating families and all past and current members of the EPIC-HIPC, and the Steen Laboratory, without whom this study would not be possible. A special recognition goes to the teams who established the unique cohorts in The Gambia, by Professor Beate Kampmann and Dr Olubukola T. Idoko at The Gambia at the London School of Hygiene and Tropical Medicine, The Gambia, and in PNG, by Anita H.J. van der Biggelaar and William S. Pomat at Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, University of Western Australia Perth, Australia.