Modulations of maternal immune cell function are critical for successful growth and development of an antigenically distinct fetus. It has been proposed that pregnancy is associated both with suppression of the adaptive immune system and a generalised maternal inflammatory response with changes in immune function resembling those associated with septicemia, and these changes are more exaggerated when pregnancies are complicated with pre-eclampsia. The nuclear factor (NF)-kappaB family of transcription factors play a significant role in immune regulation. We hypothesised therefore that if pregnancy is associated with activation of the maternal immune system, this would be supported by the activation of NF-kappaB and degradation of IkappaBalpha and beta in peripheral blood mononuclear cells (PBMCs). We demonstrate the contrary: NF-kappaB activity is suppressed in PBMCs from pregnant females and more in pre-eclampsia. The inhibition of NF-kappaB activation in pregnancy is not attributed to over-expression of IkappaBalpha or beta. In contrast, levels of IkappaBalpha and beta in cytoplasmic extracts from PBMCs in pregnancy are decreased compared with non-pregnant controls, and IkappaBalpha levels are decreased more so in pre-eclampsia. We have shown that activation of NF-kappaB in PBMCs from patients with septicemia follows the classical pathway. This pathway is differentially regulated in pregnancy. Alterations in NF-kappaB nuclear binding and IkappaBalpha levels were reproducible by culturing PBMCs in pooled pregnant serum. Taken together, these data indicate that pregnancy-specific factors exist to regulate expression of NF-kappaB/IkappaB in a pregnancy-specific manner, and may underlie one mechanism by which the fetus avoids maternal rejection throughout pregnancy.