Genetic variation of NEDD4L has been associated with hypertension and related phenotypes with conflicting results, probably attributable to gender-, age- and ethnicity-related variations in its phenotypic expression. We evaluated the association of three representative polymorphisms in NEDD4L (rs2288774, rs3865418 and rs4149601) with essential hypertension (EH) in a community-based sample of men (n = 1029) and women (n = 869) belonging to Han Chinese, Southern China, to probe whether gender interacts with NEDD4L in contributing to the risk of EH. In this population sample, rs4149601 was excluded from further analysis due to deviation from Hardy-Weinberg equilibrium. For two other variants tested, the allele frequencies and genotype distributions did not differ between cases and controls (p > 0.05) when both genders were combined. However, sex-stratified analysis revealed that the distribution of the dominant model of rs2288774 (TC + CC versus TT) and the additive and dominant (CT + TT versus CC) models of rs3865418 differed significantly between cases and controls in men (p = 0.044, 0.041 and 0.016, respectively) but not in women. After adjusting for confounding factors, logistic regression analysis showed that rs2288774 and rs3865418 (in the dominant model) were still significantly associated with EH (rs2288774: OR = 0.73, 95% CI = 0.57-0.95, p = 0.017 and rs3865418: OR = 0.71, 95% CI = 0.55-0.92, p = 0.009) in men. There was a significant interaction between the NEDD4L genotype and gender (p for interaction: 0.046 for rs2288774 and 0.033 for rs3865418). Genetic variation in NEDD4L may have sex-dependent effects in the development of EH in Han Chinese. Previous studies that ignore gender-specific effects in their design and interpretation could have failed to identify a uniform conclusion.