Objective: In postmenopausal women (PMW), the effect of a short-term course of estrogen/progestin HT on free radical oxidative stress was evaluated. In addition, HT's effect on plasma nitric oxide (NO) activity was determined as a measure of vascular endothelial function. We investigated the relationship of these markers and HT across race and the cardiovascular risk factors of smoking, diabetes and hypertension. Design: A prospective, observational study comparing preintervention and postintervention. Setting: Academic research center. Patient(s): Twenty-seven (14 African American and 13 Caucasian) PMW volunteers. Intervention (s): Six weeks of continuous, combined estrogen/progestin HT. Main Outcome Measure(s): Plasma concentrations of free 8-epi-prostaglandin F-2alpha (8-isoprostane) before and after HT were compared as a measure of oxidative stress. Nitrite, the stable oxidation metabolite of NO, was measured by the Greiss reaction after nitrate reduction to nitrite with cadmium. Results: Plasma levels of free 8-isoprostane decreased significantly after 6 weeks of HT. Although almost all subjects benefited from the reduction in free 8-isoprostane, PMW with at least one cardiovascular risk factor (n = 19) demonstrated higher free 8-isoprostane than did subjects with no risk factors. Plasma levels of nitrite increased after 6 weeks of HT, but the difference was not statistically significant. Caucasian PMW demonstrated a greater increase in plasma levels of nitrite after 6 weeks of HT as compared with African American subjects, who exhibited almost no change. Conclusion(s): Short-term administration of HT significantly reduces oxidative stress in PMW and is consistent across race. However, there was an observed racial difference in endothelial NO response to HT between African American and Caucasian PMW. (C) 2003 by American Society for Reproductive Medicine.