Introduction: Individual blood pressure (BP) response to high salt intake varies from minimal to substantial and is largely genetically determined. More than 50% of hypertensive patients are salt sensitive (SS) and respond to high salt intake by increasing their BP compared to only 10% in the normotensive population. ENaC is involved in sodium transport in the distal nephrons of the kidney as well as in the CNS in the choroid plexus and hypothalamic neurons. In turn, ENaC is controlled by the E3 ubiquitin ligase protein - NEDD4L. The functional NEDD4L SNP rs4149601 (G/A) influences the ability of NEDD4L to regulate ENaC expression and is associated with high blood pressure and salt sensitivity. We hypothesize that NEDD4L rs4149601 genotype is an independent predictor of BP response to salt intake in hypertensives. Methods: Daytime BP was measured using 24hr ABPM in 191 young (<60 years old) Caucasian hypertensives (BP ≥130/85 mmHg). 24hr urine Na and K + , blood Na + and K + , and BMI were collected. Patient genotyping for the rs4149601 (G/A) SNP was done using TaqMan MGB probe based RT PCR. Linear regression analyzed (SAS Software) the influence of urine Na + , urine K + , blood K + ,blood Na + , age, gender, and BMI on blood pressure traits. Results: In hypertensive rs4149601 G carriers (n=169), systolic BP (SBP) varied significantly with salt intake (p=0.0088) while diastolic BP did not (p=0.7198). An SBP increase of 2.34 mmHg per 50 mmol Na was observed when urine Na alone is considered. Age (p=0.0002) and blood K + (p=0.0466) were also significant determinants of SBP in patients with the G allele. Only blood K + was a significant predictor of diastolic BP (DBP) in hypertensive G allele carriers. None of the factors tested influenced either SBP or DBP in hypertensive patients who are carriers of the A allele. Conclusion: The functional NEDD4L rs4149601 SNP influences individual daytime BP response to salt intake. This result supports the hypothesis that NEDD4L rs4149601 G carriers with intact C2 domain express higher levels of ENaC and therefore are more sensitive to salt intake. Thus, NEDD4L rs4149601 polymorphism genotyping may allow for identification of hypertensive individuals who will benefit to a greater extent from reducing the amount of salt in their diet.