A genetic deficiency in renal 20‐HETE formation contributes to the development of hypertension in Dahl (S) rats. We hypothesized upregulation of CYP4A protein expression and renal 20‐HETE production improves pressure natriuresis and attenuates the development of hypertension in the S rat. Utilizing a sleeping beauty transposon construct, we generated CYP4A1 transgenic Dahl S rats. Introgression of the CYP4A1 gene, responsible for the formation of 20‐HETE, into the S genetic background, significantly increased CYP4A protein expression and 20‐HETE production by 3 and 2 fold in the kidneys of transgenic CYP4A1 rats fed high salt (HS) diet compared to S rats. MAP (177±10 mmHg) and proteinuria (295±22 mg/day) increased in S rats fed HS diet for 4 weeks, but only rose to 139±5 mmHg and 175±22 mg/day (p<0.05) in CYP4A1 transgenic rats. Pressure natriuretic and diuretic responses were 2 fold higher in CYP4A1 transgenic rats. Chronic inhibition of outer medullary 20‐HETE synthesis by renal medullary infusion of HET0016 (1 mg/kg/day) rescued the hypertensive phenotype in CYP4A1 transgenic rats (173±10 mmHg and 401±37 mg/day). These results indicate upregulation of CYP4A protein expression and 20‐HETE production attenuates the development of hypertension and renal injury and improves pressure natriuresis response in CYP4A1 transgenic Dahl S rats. AHA11POST7520052, HL36279, HL29587