Chronic exposure to low levels of lead results in sustained hypertension (HTN) in humans and experimental animals. The mechanism of lead-induced HTN remains unclear. We investigated the possible role of reactive oxygen species (ROS) and their impact on nitric oxide (NO) metabolism in lead-induced HTN. Male Sprague-Dawley rats were treated with lead (100 ppm in drinking water) for twelve weeks. They were then treated with either the potent antioxidant, lazaroid (des-methyl-tirilazad, 5 mg/kg i.p., twice daily) (Pb-Lz group) or placebo (Pb group) for two weeks and monitored for an additional two weeks. A group of normal animals served as controls (N = 6 in each group). Lead administration resulted in marked HTN together with a significant rise in plasma concentration of lipid peroxidation product, malondialdehyde (MDA, reflecting increased ROS generation) and a twofold reduction in urinary excretion of NO metabolites, that is, total nitrates and nitrites (NOx). Lazaroid therapy led to prompt normalization of blood pressure, plasma MDA and urinary NOx. In contrast, blood pressure and plasma MDA remained elevated, and recovery of urinary NOx excretion was slow with placebo therapy. No significant difference was found in creatinine clearance between the study groups during the observation period. Thus, chronic lead exposure resulted in marked HTN coupled with increased ROS production and decreased urinary NOx excretion. Administration of the potent antioxidant, lazaroid, abrogated HTN and reversed the abnormalities of plasma MDA and urinary NOx excretion, thus supporting the role of ROS in lead-induced HTN in this model.