Two isoforms of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) are present in mammals. 11 beta HSD1 interconverts biologically active cortisol and inactive cortisone, whereas 11 beta HSD2 only converts cortisol to cortisone. Placental 11 beta HSD has been proposed to protect the fetus from high level of maternal glucocorticoids. Although bidirectional activity of 11 beta HSD has been demonstrated in homogenized human placental tissues, the tissue and cellular distribution of 11 beta HSD1 has not been resolved. In this study, the cellular localization of 11 beta HSD1 protein and levels of its messenger ribonucleic acid (mRNA) in human placenta and fetal membranes were determined by immunohistochemistry and Northern blot analysis, respectively. We found that 11 beta HSD1 immunoreactivity was present in the placental extravillous intermediate trophoblasts, chorion trophoblasts, amnion epithelial cells, and stromal cells of the decidua vera. Positive staining was also observed in the endothelium of the blood vessels in both placental villous tissue and umbilical cord. However, in contrast to previous reports of immunoreactive 11 beta HSD2 localization, 11 beta HSD1 immunoreactivity was undetectable in placental syncytiotrophoblast. Using a human 11 beta HSD1 complementary DNA as probe, a 1.5-kilobase mRNA transcript was detected in the chorion, amnion, and placental tissue, with the greatest amount in the chorion. In contrast, the 1.9-kilobase mRNA of 11 beta HSD2 was observed only in the placenta, not in the chorion and amnion. The process of labor had no significant effect on levels of 11 beta HSD1 or 11 beta HSD2 mRNA in the chorion or placenta. We conclude that there is a striking difference in the tissue localization of 11 beta HSD1 and 11 beta HSD2 expression in the late gestation human placenta and fetal membranes, which may discretely determine the accessibility of bioactive glucocorticoid to specific cell types.