Inter-alpha inhibitor proteins (IAIPs) found in relatively high concentrations in human plasma are important in inflammation. IAIPs attenuate brain damage in young and adult subjects, decrease during sepsis and necrotizing enterocolitis in premature infants, and attenuate sepsis-related inflammation in newborn rats. Although a few studies have reported adult organ-specific IAIP expression, information is not available on age-dependent IAIP expression. Given evidence suggesting IAIPs attenuate brain damage in young and adult subjects, and inflammation in newborns, we examined IAIP expression in plasma, cerebral cortex (CC), choroid plexus (CP), cerebral spinal fluid (CSF), and somatic organs in fetal, newborn, and adult sheep to determine the endogenous expression patterns of these proteins during development. IAIPs (enzyme-linked immunosorbent assay) were higher in newborn and adult than fetal plasma (P < 0.05). Western immunoblot detected 125 kDa PaI (Pre-alpha Inhibitor) and 250 kDa IaI (Inter-alpha Inhibitor) in plasma, CNS, and somatic organs. PaI expression in CC and CP was higher in fetuses than newborns and adults, but IaI expression was higher in adults than fetuses and newborns. Both PaI and IaI were higher in fetal than newborn CSF. IAIPs exhibited organ-specific ontogenic patterns in placenta, liver, heart, and kidney. These results provide evidence for the first time that plasma, brain, placenta, liver, heart, and kidney express IAIPs throughout ovine development and that expression patterns are unique to each organ. Although exact functions of IAIPs in CNS and somatic tissues are not known, their presence in relatively high amounts during development suggests their potential importance in brain and organ development.