The Dahl salt-sensitive rat is a widely used model of human salt-sensitive forms of hypertension. The kidney plays an important role in the pathogenesis of Dahl salt-sensitive hypertension, but the molecular mechanisms involved remain a subject of intensive investigation. Gene expression profiling studies suggested that 11-hydroxysteroid dehydrogenase type 1 might be dys-regulated in the renal medulla of Dahl salt-sensitive rats. Additional analysis confirmed that renal medullary expression of 11-hydroxysteroid dehydrogenase type 1 was downregulated by a high salt diet in SS-13^BN rats, a consomic rat strain with reduced blood pressure salt-sensitivity, but not in Dahl salt-sensitive rats. 11-hydroxysteroid dehydrogenase type 1 is known to convert inactive 11-dehydrocorticosterone to active corticosterone. The urinary corticosterone/11-dehydrocorticosterone ratio as well as urinary excretion of corticosterone was higher in Dahl salt-sensitive rats than in SS-13^BN rats. Knockdown of renal medullary 11-hydroxysteroid dehydrogenase type 1 with small-interfering RNA attenuated the early phase of salt-induced hypertension in Dahl salt-sensitive rats and reduced urinary excretion of corticosterone. Knockdown of 11-hydroxysteroid dehydrogenase type 1 did not affect blood pressure in SS-13^BN rats. Long-term attenuation of salt-induced hypertension was achieved with small hairpin RNA targeting renal medullary 11-hydroxysteroid dehydrogenase type 1. In summary, we have demonstrated that suppression of 11-hydroxysteroid dehydrogenase type 1 expression in the renal medulla attenuates salt-induced hypertension in Dahl salt-sensitive rats.