Genetic variation is thought to contribute to etiology of metabolic syndrome (MS). Neural precursor cell expressed developmentally downregulated 4-like gene (NEDD4L) is a candidate gene for MS. This study investigated the relationship between variations of NEDD4L and MS in the Kazakh, which is an ideal population to study the genetic mechanisms of complex diseases such as MS. We screened the promoter and exons of NEDD4L in 48 Kazakh individuals with MS to identify representative variations. By genotyping the representative variations [271420T>C (rs2288774), 271454A>G (rs2288775), and 296921-296923delTTG] in the Kazakh general population, we conducted a case-control study. In female subjects, the distribution of genotypes and alleles of rs2288775 and 296921-296923delTTG differed significantly between the MS pacients and controls. In male subjects, the genotype distributions of 296921-296923delTTG were significantly different between the MS pacients and controls in the dominant model (P = 0.047). After adjustment for age, smoking, and drinking, multivariate logistic regression analysis showed that rs2288775 was significantly associated with MS [for the A/A genotype, odds ratio (OR) = 3.296, P = 0.011] in female subjects. For 296921-296923delTTG, the I/D+D/D genotype was the high-risk genotype for MS in female subjects (OR = 2.791, P = 0.035) and was a protective factor for MS in male subjects (OR = 0.580, P = 0.045). The 296921-296923delTTG variation of NEDD4L is a gender flip-flop associated with MS in Kazakh individuals. The A allele of rs2288775 may be an independent risk factor for MS in Kazakh women. The results suggest that the genetic variations of NEDD4L might be involved in the pathogenesis of MS.