Background: Preterm birth and its complications are the primary cause of death among children under the age of 5. Among the survivors, morbidity both perinatally and later in life is common. The dawn of novel technical platforms for comprehensive and sensitive analysis of protein profiles in blood has opened up new possibilities to study both health and disease with significant clinical accuracy, here used to study the preterm infant and the physiological changes of the transition from intrauterine to extrauterine life. Methods: We have performed in-depth analysis of the protein profiles of 14 extremely preterm infants using longitudinal sampling. Medical variables were integrated with extensive profiling of 448 unique protein targets. Results: The preterm infants have a distinct unified protein profile in blood directly at birth regardless of clinical background; however, the pattern changed profoundly postnatally, expressing more diverse profiles only 1 week later and further on up to term-equivalent age. Clusters of proteins depending on temporal trend were identified. Conclusion: The protein profiles and the temporal trends here described will contribute to the understanding of the physiological changes in the intrauterine−extrauterine transition, which is essential to adjust early-in-life interventions to prone a normal development in the vulnerable preterm infants. Impact: We have performed longitudinal and in-depth analysis of the protein profiles of 14 extremely preterm infants using a novel multiplex protein analysis platform.The preterm infants had a distinct unified protein profile in blood directly at birth regardless of clinical background.The pattern changed dramatically postnatally, expressing more diverse profiles only 1 week later and further on up to term-equivalent age.Certain clusters of proteins were identified depending on their temporal trend, including several liver and immune proteins.The study contributes to the understanding of the physiological changes in the intrauterine−extrauterine transition.