A retroplacental serum factor responsible for the downregulation of the MHC class II antigen expression has been described [1]. We found that maternal serum had the same property. The HLA class II modulating activity is however diminished in the presence of maternal serum as compared to retroplacental serum suggesting that the IA like inhibiting factor is released at the fetomaternal interface. After a 3-day incubation period of unrelated lymphocytes and mononuclear cord blood cells in a maternal serum pool, it was shown that the HLA Dr, the HLADp, and more significantly, the HLADq molecules were modulated. This phenomenon was more pronounced among cord blood cells. When third party lymphocytes and mononuclear cord blood cells were stimulated by Candidine or unrelated mononuclear cells in the presence of retroplacental serum, only the cellular subpopulation belonging to the CD4+ subset showed an HLADq downregulation. The molecular constituents of the MHC class II antigen expression characterizing cells belonging to other subsets remained unchanged. When the same stimulation assay was performed in the presence of a control medium (nulliparous serum), we found no changes in the MHC class II molecular constituents. When unrelated mononuclear cells and mononuclear cord blood cells were PHA stimulated in the presence of maternal and nulliparous serum, the HLADq expression of the CD8+ subset showed a significant downregulation in the maternal serum mediated stimulation assay as compared to the control stimulation test. The molecular expression of the HLA class II antigen related to the other subpopulation (CD4+, CD3+) stimulated by a mitogenic lectin remained unchanged. It is suggested that these molecular MHC class II modulations are due to a factor included in the maternal IgG reaction. Retroplacental IgG contains the highest concentration of this factor.