Activin-A is a growth factor involved in cell growth and differentiation, neuronal survival, early embryonic development and erythropoiesis. Hypoxemia is a specific trigger for increasing activin-A in fetal lamb circulation. We tested the hypothesis that fetal hypoxia induces activin-A secretion in preterm newborn infants. Fifty newborn infants with gestational ages ranging from 26 to 36 wk were enrolled in a prospective study performed at the Pediatrics, Obstetrics and Reproductive Medicine Department, University of Siena, Italy. Heparinized blood samples were obtained from the umbilical vein after cord clamping, immediately after delivery. Activin A, hypoxanthine (Hx), xanthine (Xa) plasma levels and absolute nucleated red blood cell (NRBC) count were measured. Activin-A levels (p < 0.0001) and NRBC (p < 0.0001) were significantly higher in hypoxic than in non hypoxic preterm newborns. Cord activin A levels were significantly related with Hx (taua=0.64, taub=0.64, p < 0.0001) and Xa (taua=0.56, taub=0.57, p < 0.0001) levels, NRBC ((taua=-0.45, taub=-0.46, p < 0.0001) count; pH (taua=-0.47, taub=-0.48, p < 0.0001) and base deficit (taua=-0.36, taub=0.-0.36, p = 0.0002). Preterm newborns with signs of perinatal hypoxia at birth have increased activin-A levels, suggesting that activin-A may reflect indirectly intrauterine hypoxia.