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Objectives: Currently, there is a debate regarding the roles of two functional fibrinogen-related variants (rs6050 and rs1800790) and ischemic stroke (IS). Materials and Methods: A total of 1402 subjects (834 cases and 568 controls) were genotyped for single-nucleotide polymorphisms rs6050 and rs1800790 with the ligation detection reaction method. Results: We found that the homozygous minor allele genotype (GG) of rs6050 significantly increased IS risk by 66%, whereas that of rs1800790 reduced risk by 59% (rs6050: odds ratio [OR]=1.660, 95% confidence intervals [CI]: 1.141-2.415, p=0.008; rs1800790: OR=0.413, 95% CI: 0.228-0.747, p=0.003). After stratifying IS by three common subtypes, consistent results were found in IS cases with large-artery atherosclerosis (rs6050: OR=2.116, 95% CI: 1.327-3.376, p=0.002; rs1800790: OR=0.191, 95% CI: 0.085-0.430, p=0.000), and we also observed that the homozygous minor allele genotype of rs6050 increased risk by 86% in IS cases with cardioembolism (OR=1.859, 95% CI: 1.243-2.782, p=0.003). However, a paradox of association was shown between these two sites and fibrinogen levels. In haplotype analysis, we found that those with haplotype A (major allele of rs6050 and minor allele of rs1800790) could reduce susceptibility to IS by 35% (OR=0.650, 95% CI: 0.493-0.858, p=0.002). Conclusion: Our study suggested that minor allele G of rs6050 is a significant risk factor, which can increase IS risk in the Chinese Han population, while minor allele A of rs1800790 and the haplotype A lower such risk. [ABSTRACT FROM AUTHOR]