NAD(P)H oxidase has been shown to be important in the development of salt-sensitive hypertension. Here, we show that the expression of a subunit of NAD(P)H oxidase, p67^phox, was increased in response to a high-salt diet in the outer renal medulla of the Dahl salt-sensitive (SS) rat, an animal model for human salt-sensitive hypertension. The higher expression of p67^phox, not the other subunits observed, was associated with higher NAD(P)H oxidase activity and salt sensitivity in SS rats compared with a salt-resistant strain. Genetic mutations of the SS allele of p67^phox were found in the promoter region and contributed to higher promoter activity than that of the salt-resistant strain. To verify the importance of p67^phox, we disrupted p67^phox in SS rats using zinc-finger nucleases. These rats exhibited a significant reduction of salt-sensitive hypertension and renal medullary oxidative stress and injury. p67^phox could represent a target for salt-sensitive hypertension therapy.