Interleukin-8 (IL-8/CXCL8) is widely expressed in fetal tissues although inflammatory changes are not seen. Circulating IL-8 is comprised of an endothelial-derived [ala-IL-8]77 isoform and another, more potent [ser-IL-8]72 secreted by most other cells; [ala-IL-8]77 can be converted into [ser-IL-8]72 by proteolytic removal of an N-terminal pentapeptide from [ala-IL-8]77. In this study, we show [ala-IL-8]77 is the predominant circulating isoform of IL-8 in premature neonates but not in term neonates/adults, who have [ser-IL-8]72 as the major isoform. This isoform switch from the less potent [ala-IL-8]77 to [ser-IL-8]72 correlates with a maturational increase in the neutrophil chemotactic potency of plasma IL-8. The emergence of [ser-IL-8]72 as the major isoform is likely due to increased plasma [ala-IL-8]77-convertase activity and/or changes in the cellular sources of IL-8. Developmental changes in IL-8 isoforms may serve to minimize its inflammatory effects in the fetus and also provide a mechanism to restore its full activity after birth. © 2009 Elsevier Ltd. All rights reserved.