Absence of class II MHC antigens from human syncytiotrophoblast is a common finding in normal-term placentae. Since chronic villitis of unestablished etiology is a placental lesion frequently found in normal and abnormal term placentae, and fetal stem vessels are MHC class II-positive in these lesions, we asked if syncytiotrophoblast in villitis is reactive for MHC class II antigens. We found segments of syncytiotrophoblast that were reactive for the MHC class II HLA-DR, DP, and DQ antigens in villitis areas of normal-term placentae and in placentae from women with a history of recurrent spontaneous abortions. This reactivity was not due to trophoblast replacement by activated macrophages, though the possibility of crossreactive antigens and binding of soluble MHC class II antigens by receptors developed in areas of villitis could not be excluded. MHC class II antigen expression on syncytiotrophoblast could be due to cytokine release from activated macrophages and helper T lymphocytes which we have previously described in areas of villitis of unestablished etiology.