Development and progression of end-organ damage in hypertension have been associated with increased oxidative stress. Superoxide anion accumulation has been reported in deoxycorticosterone acetate (DOCA)-salt hypertension, in which endothelin-1 plays an important role in cardiovascular damage. We hypothesized that blockade of ET _A receptors in DOCA-salt rats would decrease oxidative stress. Both systolic blood pressure (SBP, 210±9 mm Hg; P <0.05) and vascular superoxide generation in vivo were increased in DOCA-salt (44.9±10.3% of ethidium bromide–positive nuclei; P <0.05) versus control uninephrectomized (UniNx) rats (118±3 mm Hg; 18.5±3%, respectively). In DOCA-salt rats, the ET _A antagonist BMS 182874 (40 mg/kg per day PO) lowered SBP (170±4 versus UniNx, 120±3 mm Hg) and normalized superoxide production (21.7±6 versus UniNx, 11.9±7%). Vitamin E (200 mg/kg per day PO) decreased superoxide formation in DOCA-salt rats (18.8±7%) but did not alter SBP. Oxidative stress in nonstimulated circulating polymorphonuclear cells (PMNs) or in PMNs treated with zymosan, an inducer of superoxide release, was similar in DOCA-salt and UniNx groups. Superoxide formation by PMNs was unaffected by treatment with BMS 182874. Western blot analysis showed increased nitrotyrosine-containing proteins in mesenteric vessels from DOCA-salt compared with UniNX. Treatment with either BMS 182874 or vitamin E abolished the differences in vascular nitrotyrosine-containing proteins between DOCA-salt and UniNX. Maximal relaxation to acetylcholine was decreased in DOCA-salt aortas (75.8±4.2% versus UniNx, 95.4±1.9%, P <0.05). BMS 182874 treatment increased acetylcholine-induced relaxation in DOCA-salt aortas to 93.5±4.5%. These in vivo findings indicate that increased vascular superoxide production is associated with activation of the endothelin system through ET _A receptors in DOCA-salt hypertension, in apparently blood pressure–independent fashion.