Background Excessive fetal exposure to glucocorticoids has been implicated in the etiology of adult metabolic and cardiovascular disease. Placental 11-hydroxysteroid dehydrogenase type 2 (11-HSD2) may protect the fetus from excessive glucocorticoid exposure. Maternal stress may be accompanied by elevated levels of cortisol as well as increased pro-inflammatory cytokines, interleukin-1 (IL-1), IL-6 and tumor necrosis factor- (TNF). Hypothesis Pro-inflammatory cytokines inhibit human placental 11-HSD activity. Methods Explant cultures of term human placental villi were incubated in the presence or absence of 10 µM IL-1, IL-6 or TNF, with or without agonists or antagonists of intracellular Ca⁺⁺ and adenylyl cyclase. Activity for 11-HSD2 was estimated using a radioisotope assay and mRNA measured using quantitative reverse transcription-polymerase chain reaction. Results All cytokines significantly (P 0.05) reduced 11-HSD2 activity (> 75% suppression) with maximal inhibition occurring within 2 h and maintained for at least 24 h. The IL-1-induced inhibitory activity was attenuated using a calcium channel blocker (nifedipine), an intracellular Ca⁺⁺ antagonist (TMB-8), or the adenylyl cyclase stimulant, forskolin. Conversely 11-HSD2 activity was diminished in the presence of the calcium ionophore A23187 or the adenylyl cyclase inhibitor SQ22536. Messenger RNA levels for 11-HSD 2 were not changed by any of the treatments. Conclusions Pro-inflammatory cytokines inhibit human placental 11-HSD2 activity through a mechanism that involves increased intracellular Ca++ and inhibition of adenylyl cyclase. This could result in excessive fetal exposure to maternal cortisol. This mechanism might mediate part of the increased risk of metabolic and cardiovascular disease in adult offspring.