OBJECTIVE: Several clinical studies have reported that xanthine oxidoreductase inhibitors have antihypertensive and renal protective effects but their mechanisms have not been fully determined. This study aims to clarify these mechanisms by examining the effects of febuxostat, which is a novel selective xanthine oxidoreductase inhibitor, in Dahl salt-sensitive rats. METHODS: Eight-week-old male Dahl salt-sensitive rats were fed a normal salt (0.6% NaCl) or high salt (8% NaCl) diet for 8 weeks. A portion of the rats that were fed high salt diet were treated with febuxostat (3 mg/kg per day) simultaneously. Additionally, acute effects of febuxostat (3 mg/kg per day) were examined after high salt diet feeding for 4 or 8 weeks. RESULTS: Treatment with febuxostat for 8 weeks attenuated high salt diet-induced hypertension, renal dysfunction, glomerular injury, and renal interstitial fibrosis. Febuxostat treatment reduced urinary excretion of H2O2 and malondialdehyde and renal thiobarbituric acid reactive substances content. High salt diet increased xanthine oxidoreductase activity and expression in the proximal tubules and medullary interstitium. Febuxostat completely inhibited xanthine oxidoreductase activity and attenuated the high salt diet-increased xanthine oxidoreductase expression. Febuxostat transiently increased urine volume and Na+ excretion without change in blood pressure or urinary creatinine excretion after high salt diet feeding for 4 or 8 weeks. CONCLUSION: Febuxostat ameliorates high salt diet-induced hypertension and renal damage with a reduction of renal oxidative stress in Dahl salt-sensitive rats. The antihypertensive effect of febuxostat may be mediated in part by diuretic and natriuretic action.