Natriuretic peptide precursor A (NPPA) is synthesized, stored, and released by atrial myocytes. Previous studies have shown that NPPA plays a significant role in the regulation of coronary circulation and in atherosclerosis. Rs5065 NPPA gene polymorphism leads to the translation of NPPA with two additional arginines and has been suggested to be associated with salt-sensitive hypertension. The purpose of the present study was to investigate the relationship between the rs5065 NPPA gene polymorphism and the risk of coronary heart disease (CHD) in Chinese Han population. We genotyped the single nucleotide polymorphism (SNP) rs5065 NPPA in the human NPPA gene in 1861 sex- and age-matched subjects, comprising of 904 CHD cases and 957 controls of Chinese Han population. Genotyping of SNP was performed with Taqman SNP allelic discrimination assays by means of an ABI 7900HT. Our study showed that the frequencies of rs5065 NPPA C allele in the case and the control groups were 0.012 and 0.005, respectively. There was significant difference in C allele frequency distribution between the two groups (OR=2.607, 95% CI: 1.197-5.678, P= 0.012). In the case group, there was significant difference between smokers and nonsmokers with subjects carrying C allele (P=0.037), and no significant difference in gender, age, fasting total cholesterol (TC), triglycerides (TG), fasting plasma glucose (FPG), body mass index (BMI), and blood pressure (BP) between the cases and the controls (P>0.05). Our results suggest that the C allele of rs5065 NPPA gene polymorphism may be associated with the risk of CHD.