During normal pregnancy, in contrast to preeclampsia, plasma hemopexin activity is increased together with a decreased vascular angiotensin II receptor (AT1) expression. We now tested the hypothesis that hemopexin can downregulate the AT1 receptor in vitro. Analysis of human monocytes or endothelial cells by flow cytometry showed decreased membrane density of AT1 exclusively after incubation with active hemopexin, whereas in supernatants of these cell cultures, AT1 molecules could be detected (dot blotting). Also, diminished AT1 was observed in endothelial cell lysates after contact with hemopexin (Western blotting). Hemopexin also induced extracellular signal–regulated kinase 1/2 pathway inhibition in cells after stimulation with angiotensin II in vitro, indicating downregulation of AT1 by hemopexin. In addition, functional loss of AT1 occurred after incubation of rat aortic rings with active hemopexin, as reflected by decreased contraction of the aortic rings on stimulation with angiotensin II. It was further demonstrated that plasma from normal pregnant women decreased the AT1 receptor expression on monocytes as compared with plasma from nonpregnant women or preeclamptic women. Finally, it was shown that plasma hemopexin activity increases during normal gestation from week 10 onward. We concluded that active hemopexin is able to downregulate the AT1 receptor in human monocytes, endothelial cells, and rat aortic rings. We propose that the physiological role of enhanced hemopexin activity during healthy pregnancy is to downregulate the vascular AT1 receptor, promoting an expanded vascular bed. Inhibition of hemopexin activity during preeclampsia may result in an enhanced AT1 receptor expression and a contracted vascular bed.