Human maternal serum has been shown to down-regulate the expression of MHC class II antigen in three distinct circumstances. Cord blood mononuclear cells, incubated in the mother's own serum, showed significant modulation of class II antigen expression. This was also the case for unrelated donor lymphocytes, incubated in pooled maternal serum. One neoplastic line (Daudi) was further shown to down-regulate class II antigen expression. In this last case, the down-regulating effect persisted over a 10-day period during which maternal serum was renewed regularly. Retroplacental serum was more MHC class II-inhibiting than peripheral serum. This down-regulating effect does not apply to maternal lymphocytes. The inhibitory effect is thought to be due to a factor, yet to be defined, included in the maternal IgG fraction. Regular assays made throughout pregnancy showed that the class II inhibiting component appears early (5th week), reaches its peak value at the 12th week, and disappears 2 or 3 weeks after delivery.