Pregnancy-induced structural changes in spiral arteries seem to be a prerequisite for successful fetal outcome in humans. It is unknown whether these changes also occur in other preplacental vessels (radial and arcuate arteries) in normal pregnancies. Since the radial and arcuate arteries need to dilate in order to accommodate the increase in placental blood flow during pregnancy, it is expected that they are also invaded by trophoblast and respond with structural changes. The objective of the present study was to evaluate the extent of trophoblast invasion in the guinea-pig preplacental vasculature and its effect on the vascular structure of mesometrial, myometrial and arcade arteries. Under general anaesthesia the vascular system of non- (n = 4), mid- (n = 4) and late- (n = 8) pregnant guinea-pigs was fixed by immersion or perfusion. Cross-sections of immersion-fixed mesometrial and arcade arteries were stained with toluidine blue. Cross-sections of perfusion-fixed mesometrial, myometrial and arcade arteries were stained with haematoxylin-eosin, Elastica van Gieson staining and antibodies against alpha-smooth-muscle-actin (ASMA), cytokeratin and factor VIII, to detect vascular smooth muscle, trophoblastic, and endothelial cells, respectively. In addition, the external and internal vascular circumference of sections from perfusion-fixed tissue was determined. All cross-sections were evaluated by light microscopy. In the course of pregnancy, progressive endothelial swelling, disappearance of the elastic lamina interna and disarrangement of the tunica media were observed in the myometrial and throughout the mesometrial arteries up to the junction with the arcade arteries. These changes coincided the migration of keratin-positive staining giant cells. It is concluded that in normal guinea-pig pregnancy, structural changes occur in the entire mesometrial artery and at least a part of the myometrial artery, although such changes were not seen in the arcade artery.