Background. Evidence indicates that soluble forms of amyloid- (A) are vasoactive, which may contribute to cerebrovascular dysfunction noted in patients with Alzheimer's Disease and cerebral amyloid angiopathy. The effects of soluble A on penetrating cerebral arterioles - the vessels most responsible for controlling cerebrovascular resistance - have not been studied. Results. Freshly dissolved A1-40 and A1-42, but not the reverse peptide A40-1 constricted isolated rat penetrating arterioles and diminished dilation to adenosine tri-phosphate (ATP). A1-42 also enhanced ATP-induced vessel constriction. A1-40 diminished arteriolar myogenic response, and an anti-A antibody reduced A1-40 induced arteriolar constriction. Prolonged A exposure in vessels of Tg2576 mice resulted in a marked age-dependent effect on ATP-induced vascular responses. Vessels from 6 month old Tg2576 mice had reduced vascular responses whereas these were absent from 12 month old animals. A1-40 and A1-42 acutely increased production of reactive oxygen species (ROS) in cultured rat cerebro-microvascular cells. The radical scavenger MnTBAP attenuated this A-induced oxidative stress and A1-40-induced constriction in rat arterioles. Conclusions. Our results suggest that soluble A1-40 and A1-42 directly affect the vasomotor regulation of isolated rodent penetrating arterioles, and that ROS partially mediate these effects. Once insoluble A deposits are present, arteriolar reactivity is greatly diminished.