To investigate whether natriuretic peptide receptor-C (NPR3) gene polymorphisms were associated with ischemic stroke (IS) and hypertension (a conventional risk factor for stroke), we conducted a case-control study in Chinese Han population. We found that rs696831, located in intron 2, was associated with IS. In addition, we found that rs16890208 and rs700925, in linkage disequilibrium (LD) with each other in intron 3, were associated with hypertension. The A allele of the rs16890208, T allele of the rs700925, and the AT haplotype, derived from rs16890208 and rs700925, increased the risk of hypertension with odds ratios (ORs) of 1.74 (95% CI = 1.23-2.47), 1.72 (95% CI = 1.21-2.42), and 1.54 (95% CI = 1.14-2.08), respectively. Further, we found that rs11745562 and rs2270915, in LD with each other in intron 5 and exon 8, were associated with hypertension. The A allele of the rs11745562 and the G allele of the rs2270915 increased the risk of hypertension with ORs of 1.53 (95% CI = 1.07-2.19) and 1.55 (95% CI = 1.08-2.22), respectively. Therefore, we provided novel evidences that polymorphisms or haplotype in NPR3 gene may influence the risk of IS or hypertension independently in Chinese population.