Three different protocols were carried out to evaluate the effect of magnesium sulfate (MgSO4) on the capacity of the normal human placenta to secrete TNF-alpha and IL-6 in presence and absence of angiotensin II (AII). Ten placentas were perfused with MgSO4 (6-7 mg%) or medium in the absence or presence of AII. Perfusate samples from fetal and maternal sites were collected and examined for IL-6 and TNF-alpha by ELISA. The maternal site of placentas exposed to AII showed only basal levels of TNF-alpha. Exposure of the placentas to MgSO4 resulted in significant increase in TNF-alpha and IL-6 in the maternal site (p < 0.05). However, the effect of MgSO4 was significantly attenuated by AII injected in presence of MgSO4. TNF-alpha and IL-6 levels in the maternal site significantly decreased (p < 0.05). The fetal site of the placentas exposed to MgSO4 or AII separately showed only basal levels of TNF-alpha and IL-6. However, TNF-alpha and IL-6 levels were significantly higher after injection of AII in the presence of MgSO4 compared to TNF-alpha levels in the fetal site of placentas exposed to AII alone (p < 0.05) or MgSO4 alone (p < 0.01). MgSO4 induced the ability of the placental maternal site to secrete TNF-alpha and IL-6. In the presence of both MgSO4 and AII, the effect of MgSO4 on the maternal site was significantly reduced. However, in the fetal site, MgSO4 alone had no significant effect on TNF-alpha and IL-6 levels although, in presence of AII and MgSO4, there was a significant increase in TNF-alpha and IL-6 levels. Elevation of TNF-alpha and IL-6 in the fetal compartment, which may affect fetal brain growth and development and placental function should be considered before administration of MgSO4 during pregnancy.