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Immunomediators seem to have a central role in the immune system of both human milk and newborn infants. CD31/PECAM-1 is an adhesion molecule, member of Ig gene superfamily, mediating cell–cell adhesion in both homophilic and heterophilic ways. Levels of the soluble form of PECAM-1 (sPECAM-1) were evaluated on the 2nd and 5th day postpartum in breast milk and serum paired samples from 20 lactating women as well as in time-matched serum from their single, term, healthy neonates. Concentrations of sPECAM-1 in breast milk (median, range) on both the 2nd (2.05 ng/ml, 0.0–7.2) and 5th day postpartum (0.89 ng/ml, 0.0–3.6) were about 10 and 20 times lower than those (mean±SD) in controls (healthy adults) (19.83±5.17, p<7×10−8), showing a significant fall from the 2nd to the 5th day postpartum (p<0.0005). Maternal serum sPECAM-1 values (mean±SD) were significantly lower on the 2nd day postpartum (14.21±5.15 ng/ml) than those in controls (p<0.002), but reached control values on the 5th day postpartum after a significant rise (p<0.0075). Neonatal serum sPECAM-1 values with no significant difference between the 2nd (14.4±4.11 ng/ml) and 5th day of life (14.54±4.99 ng/ml) were significantly lower than those in controls (p<0.002). Values of sPECAM-1 in milk and sera of lactating mothers and their neonates on the 2nd day postpartum depended on the mode of delivery, being significantly lower after caesarean section (p<0.034, p<0.0075 and p<0.035, respectively). In conclusion, our findings in the early postpartum period demonstrate that: (a) sPECAM-1 is present in human milk in low and decreasing concentrations; (b) the shedding of sPECAM-1 is an established component of the neonatal immune system from birth, though in lower concentrations than in adults, possibly reflecting its immaturity; and (c) the mode of delivery has a significant effect on sPECAM-1 values in milk and sera of lactating mothers and their neonates; the lower values after caesarean section may reveal a deranged endothelial homeostasis. [Copyright &y& Elsevier]