OBJECTIVE: The capability of the protein NEDD4L to reduce renal tubular expression of epithelial Na+ channel (ENaC) is influenced by a functional rs4149601 G→A NEDD4L polymorphism. As diuretics and β-blockers inhibit renal sodium reabsorption and renin release, respectively, we hypothesized that the β-blocker or diuretic-induced blood pressure reduction and prevention of cardiovascular disease would be greater in patients with the highest ENaC expression (rs4149601 G-allele), whereas there would be no such genetically mediated differences in treatment efficacy among patients treated with the vasodilator diltiazem. METHODS: We related rs4149601 status to 6-month blood pressure reduction and risk of cardiovascular events in 5152 hypertensive patients (DBP ≥ 100 mmHg) from the Nordic Diltiazem Study (NORDIL) randomized to either β-blocker and/or diuretic-based treatment or diltiazem-based treatment. RESULTS: In patients on β-blocker or diuretic monotherapy, carriers of the G-allele had greater SBP reduction (19.5 ± 16.8 vs. 15.0 ± 19.3 mmHg, P < 0.001) and DBP reduction (15.4 ± 8.3vs. 14.1 ± 8.4 mmHg, P = 0.02) and during 4.5 years of follow-up among patients randomized to β-blockers and/or diuretics, carriers of the G-allele had greater protection from cardiovascular events [relative risk (RR) = 0.52, 95% confidence interval (CI) = 0.36-0.74, P < 0.001] as compared to AA homozygotes. Within the diltiazem group, there was no difference in blood pressure reduction or risk of cardiovascular events according to genotype. CONCLUSION: The functional NEDD4L rs4149601 polymorphism influences the efficacy of β-blocker and/or diuretic-based antihypertensive treatment both in terms of blood pressure reduction and cardiovascular disease protection, whereas diltiazem-based antihypertensive treatment efficacy is not influenced by this NEDD4L polymorphism.