In pregnancies complicated by intrauterine growth restriction (IUGR), the villous trophoblast shows increased apoptosis and immature cytotrophoblasts (CT) may be exposed to both higher or lower oxygen levels than normal placentae. We propose that villous CT undergo higher frequencies of apoptosis at extreme oxygen tensions. The apoptosis of CT isolated from normal term placentae was examined before culture and after 24 h of culture at different oxygen tensions with or without TNFalpha. The apoptosis frequencies of cells cultured for 24 h at O2 levels of approximately 15 mm and approximately 38 mm Hg were similar to the frequency before culture. Both constitutive and TNFalpha-induced apoptosis and cell loss were highest at low (<10 mm Hg) and high ( approximately 140 mm Hg) oxygen tensions. Further, the ratios of induced to constitutive apoptosis, constant from approximately 15 mm to approximately 140 mm Hg, indicate induced apoptosis to be rather insensitive to changes in oxygen levels. These results show that primary villous trophoblasts from normal placentae undergo minimal apoptosis unless subjected to extreme oxygen tensions <15 mm or 140 mm Hg. The results indicate that normal villous trophoblasts are remarkably resistant to hypoxia-induced apoptosis.