Background Hyperplasia suppressor gene/Mitofusion-2 (HSG/Mfn2) is a novel hypertension-related gene, which can inhibit vascular smooth muscle cell proliferation and regulate mitochondrial fusion.However, the relationship between the HSG/Mfn2 variants and hypertension has not been extensively studied.The objective of the present study was to evaluate the association of the HSG/Mfu2 gene and hypertension using a haplotype-based case-control study in northern Han Chinese population.Methodology/Principal Findings A total of 626 hypertensive patients (EH group) and 618 normotensive subjects (NT group) were recruited in this study.Genotyping was performed to identify the six single-nucleotide polymorphisms (SNPs) of HSG/Mfn2 gene (rs3753579, rs1810563, rs2295281, rs2236057, rs2236058 and rs7550536).Significant associations were found in allele comparison (OR =0.776, 95% CI =0.636-0.948, P =0.013), in recessive genetic model (OR =0.642, 95% CI =0.457-0.902, P =0.011), in homozygote comparison (OR =0.592, 95% CI =0.396-0.885, P =0.01), and in additive genetic model (OR =0.775, 95% CI =0.634-0.948, P =0.013) for rs3753579 polymorphism.Rs2236058 and rs7550536 polymorphisms showed a similar association with hypertension.No significant association could be found between rs 1810563, rs2295281 and rs2236057 polymorphisms and EH risk.Stratification analysis by gender showed that significant association between rs3753579, rs1810563, rs2236058 and rs7550536 polymorphisms and EH risk could be found in males, but not in females.Haplotype analysis demonstrated that C-C-C-A-C-T haplotype had an increased risk for hypertension (OR =1.276, 95%CI =1.04-1.565, P =0.02) in males.However, T-T-T-G-G-G haplotype was shown to be a protective haplotype (OR =0.794, 95%CI =0.645-0.978; P =0.03) in males.Conclusions/Significance We revealed that the HSG/Mfn2 rs3753579, rs2236058 and rs7550536 polymorphisms might decrease the risk for EH in northem Han Chinese population.