The microvillous membrane (MVM) potential (Em) of first trimester human placental villi was measured and compared with that in villi from term human placentas. The median Em in first trimester villi (-28 mV) was significantly more negative than that at term (-21 mV; P < 0.001). The median Em measured in villi from early (weeks 6-11) first trimester (-32 mV) was significantly more negative than that in late (weeks 12 and 13) first trimester villi (-24 mV; P < 0.001). Elevating extracellular KCl concentration induced a significant depolarization of Em in both first trimester and term villi (P < 0.05 and P < 0.001, respectively). The magnitude of this depolarization was greater in first trimester than at term, indicating that the ion conductance of the MVM changes with gestation. Exposure to ouabain induced a significant depolarization of Em (3 mV: P < 0.05) in first trimester villi but had little effect at term. These results suggest that microvillous membrane electrophysiology changes with placental development. An alteration in the relative K+:Cl- conductance of the MVM is likely to be a major contributor to the change in the magnitude of Em.