Pathologic formation of reactive oxygen species (ROS) within the coronary circulation has been hypothesized to mediate some clinical manifestations of ischemic heart disease (IHD) by interfering with physiologic regulation of coronary tone. To determine the degree to which coronary tone responds to acute changes in ambient levels of oxidants and anti-oxidants in vivo in a clinical setting, we measured the effect of an acute oxidative stress (breathing 100% oxygen) on coronary capacitance artery diameter (quantitative angiography) and blood flow velocity through the coronary microcirculation (intra-coronary Doppler ultrasonography) before and after treatment with the antioxidant vitamin C (3 grams intravenous infusion) in n=12 IHD patients undergoing a clinical coronary interventional procedure. Relative to room air breathing, 100% oxygen breathing promptly reduced coronary blood flow velocity by 20% and increased coronary resistance by 23%, without significantly changing the diameter of capacitance arteries. Vitamin C administration promptly restored coronary flow velocity and resistance to a slightly supra-basal level, and prevented the re-induction of coronary constriction upon re-challenge with 100% oxygen. This suggests that acute oxidative stress produces prompt and substantial changes in coronary resistance and blood flow in a clinical setting in patients with IHD, and that these changes are mediated by vitamin C-quenchable substances acting on the coronary microcirculation. This observation may have relevance for clinical practice.