Dahl salt-sensitive (SS) and consomic, salt-resistant SS.13^BN rats possess substantial differences in blood pressure salt-sensitivity even with highly similar genetic backgrounds. The present study examined whether increased oxidative stress, particularly H₂O₂, in the renal medulla of SS rats contributes to these differences. Blood pressure (BP) was measured using femoral arterial catheters in 3 groups of rats; 1) 12 week old SS and consomic SS.13^BN rats fed a 0.4% NaCl diet, 2) SS rats fed a 4% NaCl diet and chronically infused with saline or catalase (6.9µg/kg/min) directly into the renal medulla, and 3) SS.13^BN fed high salt (4%) and infused with saline or H₂O₂ (347nmol/kg/min) into the renal medullary interstitium. After chronic BP measurements, renal medullary interstitial [H₂O₂] was collected by microdialysis and analyzed with Amplex^TMred. BP and [H₂O₂] were both significantly higher in SS (126±3mmHg, 145±17nM) vs. SS.13^BN rats (116±2mmHg, 56±14nM) fed a 0.4% diet. Renal interstitial catalase infusion significantly decreased [H₂O₂] (96±41nM vs 297±52nM) and attenuated the hypertension (146±2mmHg, catalase vs 163±4mmHg, saline) in SS rats after 5 days of high salt (4%). H₂O₂ infused into the renal medulla of consomic SS.13^BN fed high salt (4%) for 7 days accentuated the salt-sensitivity (145±2 mmHg, H₂O₂ vs 134±1mmHg, saline). [H₂O₂] was also increased in the treated group (83±1 nM, H₂O₂ vs. 44±9nM, saline). These data show that medullary production of H₂O₂ may contribute to salt-induced hypertension in SS rats and that chromosome 13 of the Brown Norway contains gene(s) that protect against renal medullary oxidant stress.