OBJECTIVE: We aimed to investigate the relationship between day-1 hypoproteinemia and severe adverse outcome (SAO) in very preterm infants admitted to the neonatal intensive care unit (NICU). STUDY DESIGN: Retrospective study of all patients born from 24 to 31 weeks gestation and cared for in our NICU over an 8-year period. Infants were excluded if the serum protein value on the first day of life was not available. RESULT: A total of 913 patients were included. In all, 14.6% presented with SAO (death or severe neurological injury on cranial ultrasound). Hypoproteinemia (total protein level \textless40 g l(-1)) on day 1 of life occurred in 19.5 % of all patients. The rate of SAO was 33.7% in patients with hypoproteinemia and 9.9% in those with normoproteinemia (P\textless0.0001). Logistic and multiple regression analysis confirmed that the association hypoproteinemia-SAO remained significant after adjustment for the other major predictors of outcome present at baseline (odds ratio 3.4; 95% confidence interval 2.1-5.4; P\textless0.0001). CONCLUSION: Hypoproteinemia was highly associated with SAO in this cohort of critically ill preterm infants. We are unable to explain the link between hypoproteinemia and adverse outcome in our population. This investigation serves as a hypothesis-generating report of a large preterm infants sample, and suggests the need to assess the predictive accuracy for adverse outcome of hypoproteinemia in future prospective studies.