CYP4F2 acts primarily as an enzyme that converts arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a metabolite involved in the regulation of blood pressure in humans. The aim of the present study was to assess the association between the human CYP4F2 gene and essential hypertension (EH) using a haplotype-based case-control study that included separate analysis of the two gender groups. The 249 EH patients and 238 age-matched controls were genotyped for 5 single-nucleotide polymorphisms (SNPs) of the human CYP4F2 gene (rs3093105, rs3093135, rs1558139, rs2108622, rs3093200). Data were analyzed for 3 separate groups: all subjects, and men and women separately. For the total population and for male subjects, the distribution of the dominant model of rs1558139 (CC vs. CT+TT) differed significantly between the EH patients and control subjects (p=0.037 and p=0.005, respectively), with a higher percentage of EH patients showing the CC genotype. Logistic regression showed that, for men, the CC genotype of rs1558139 was more prevalent in the EH patients than in the control subjects (p=0.026), while, for the total population, the difference disappeared (p=0.247). For men, the overall distribution of the haplotypes was significantly different between the EH patients and the control subjects (p=0.042), and the frequency of the T-T-G haplotype was also significantly lower for EH patients than for control subjects (p=0.009). In conclusion, the present results indicate that rs1558139 might be a genetic marker for EH and the T-T-G haplotype might be a protective genetic marker for EH in Japanese men.