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Background: A causal relationship between plasma cholesterol and blood pressure remains poorly understood. It has been postulated that the decrease in nitric oxide (NO) availability is a potential mechanism by which hypercholesterolemia may stimulate blood pressure elevation. However, evidence supporting the role of the L-arginine-NO pathway on the relationship between hypertension and hypercholesterolemia is still lacking., Methods and Results: We tested for an association of the expressed NO synthase (eNOS) Glu298Asp gene variant and plasma levels of lipids and lipoproteins in the determination of systolic blood pressure levels in a 1577 individuals randomly selected from the general population. Significant interactions could be disclosed either between the Glu298Asp gene variant and total-cholesterol (p = 0.02), log-transformed triglycerides (p = 0.004) or non-HDL-cholesterol (p = 0.003) in the determination of systolic blood pressure. In addition, although the presence of the AspAsp genotype did not significantly increase the risk of hypertension in individuals in the 50% lowest percentile of total-cholesterol, presence of this genotype significantly increased the risk of hypertension in individuals in the 50% highest percentile. Finally, in a multiple logistic regression model adjusting for age, sex, diabetes, ethnicity, smoking status and BMI, the AspAsp genotype significantly increased the risk of hypertension only in individuals with total-cholesterol above 209 mg/dL (p = 0.05, odds ratios (OR) = 2.0)., Conclusion: Taken together, these results provide evidence supporting the role of the eNOS Glu298Asp gene variant in modulating blood pressure through a relationship with lipid levels.