BACKGROUND: The IL-33/ST2 pathway plays a crucial role in the development of essential hypertension (EH). This study aimed to investigate the relationship between EH and genetic variations in this pathway in the Chinese Han population. METHODS: A total of 1,151 EH patients and 1,135 healthy controls were included in the study. Sixteen single nucleotide polymorphisms (SNPs) in the interleukin-33 (IL-33) and interleukin-1receptor associated protein (IL-1RAcP) genes were genotyped using the Sequenom MassArray and TaqMan assays. Genotype and allele frequencies were compared between the EH patients and controls using logistic regression analysis. RESULTS: The rs16865597 SNP in the IL-1RAcP gene was found to be associated with the risk of EH. Specifically, the presence of the C allele of rs16865597 was negatively correlated with EH susceptibility in both the additive model (P = 0.014, OR = 0.75, 95% CI = 0.59-0.94) and the recessive model (P = 0.011, OR = 0.72, 95% CI = 0.56-0.93). Additionally, rs16865597 was linked to a reduced risk of EH in specific subgroups, including males (OR add = 0.73, 95% CI = 0.56-0.94, P = 0.015), nonsmokers (OR add = 0.72, 95% CI = 0.54-0.96, P = 0.023), nondrinkers (OR add = 0.70, 95% CI = 0.53-0.93, P = 0.013), and individuals with low BMI (OR add = 0.69, 95% CI = 0.51-0.92, P = 0.013). Moreover, the C genotype of rs16865597 was strongly associated with higher interleukin-10 levels in vivo. CONCLUSION: The rs16865597 SNP is significantly associated with a reduced risk of EH in the Chinese Han population, potentially due to its role in immune regulation.