Context: Surfactant is a successful therapeutic based on supplementing preterm infants with a substance that would normally have been up-regulated in late gestation. Although prematurity is associated with oxidative stress, no effective antioxidant therapy has yet been identified. Objective: Our objective was to identify endogenous antioxidants involved in fetal preparation for birth. Design: We performed transcript profiling of fetal rat lung and intestine at 16 d gestational age (dGA) and 20 dGA with out-of-sample validation. Gene expression was then measured in fetal sheep tissues, comparing 1) advancing GA, 2) exogenous maternal dexamethasone (compared with saline, at 130 dGA), and 3) fetal adrenalectomy at 115–118 d on levels at term. Protein levels were compared in human umbilical cord serum using Western blot. Results: Four transcripts were up-regulated more than 20-fold on the array in both rat lung and intestine. One of these, paraoxonase-3 (Pon3), had been identified as a putative circulating antioxidant. Up-regulation of Pon3 mRNA in rat lung, intestine, and liver was confirmed in siblings (all P 0.001). Pon3 mRNA levels in fetal sheep lung and intestine increased 5.1- and 5.3-fold, respectively (both P0.001) between 100 and 145dGAand were strongly correlated with plasma cortisol (both P 0.001). Fetal sheep pulmonary Pon3 transcript level was increased 55% (P 0.01) by dexamethasoneandreduced74%( P0.001) by adrenalectomy.Termhumaninfantshadmorethan 6-fold higher umbilical cord serum levels of Pon3 than preterm (24–28 wk GA) infants (P 0.001). Conclusions: Pon3, a putative circulating antioxidant, was systemically up-regulated in lategestation rat, sheep, and human fetuses and is a candidate therapeutic in preterm human infants.