The vitamin K epoxide reductase subunit 1 gene (VKORC1) plays a key role in vitamin K recycling, and there is a close association between VKORC1 gene single-nucleotide polymorphisms (SNPs) and the required dose of warfarin, an anticoagulant. However, the association between VKORC1 SNPs and ischemic cerebrovascular disease (ICVD) has not been defined. This case-control study involved 370 patients with ICVD and 408 healthy individuals (controls) from Chinese Han population. Two VKORC1 gene SNPs (1639A/G and 1173T/C) were genotyped by PCR-RFLP method. The G allele frequencies of the 1639A/G locus and C allele frequencies of the 1173T/C locus were higher in the ICVD group than in the control group (p = 0.014 and p = 0.008, respectively). Haplotype analysis showed that 1639G-1173C was associated with an increased risk of ICVD (odds ratio (OR) = 1.163, 95 % confidence interval (CI) = 1.137~2.288), while 1639A-1173T was associated with decreased risk of ICVD (OR = 0.620, 95 % CI = 0.437~0.880). Our findings suggested that individuals carrying the 1639G or 1173C allele might be at increased risk for ICVD. Furthermore, the 1639G-1173C haplotype was a risk factor for ICVD, and 1639A-1173T was a protective factor in Chinese Han population.