Studies of the human placental vasculature suggest a low resistance circulation. Using wire myography, endothelial-dependent relaxation of human chorionic plate arteries has been difficult to demonstrate with any consistency. However, histamine has been suggested to relax placental vessels in the perfused organ in vitro. Here we aimed to demonstrate endothelial-dependent relaxation to histamine under physiological conditions of stretch and oxygenation. Histamine administration to pre-contracted arteries induced a triphasic response; an initial contraction followed by a dilatation which stabilized to a significant relaxation compared to time control arteries. Relaxation was partially inhibited by blockers of endothelial-dependent relaxation pathways. The initial contraction was abolished by H1-receptor blockade with mepyramine. The relaxation was significantly reduced by H2-receptor blockade with famotidine but only abolished in the presence of both H1- and H2-receptor antagonists. In conclusion, histamine induced contraction and relaxation of human chorionic plate arteries. Our data suggest that contraction is mediated by activation of H1-receptors. Relaxation occurs directly, via activation of H2-receptors on vascular smooth muscle cells, and indirectly via H1-receptor stimulation of endothelial-dependent relaxation. © 2007 Elsevier Ltd. All rights reserved.