Genetic variants of plasminogen activator inhibitor type 1 (PAI-1) gene have been suggested to influence the PAI-1 transcription activity and PAI-1 levels as well as might be involved in the pathophysiology of stroke. The aims of this study are to investigate whether the polymorphisms at the PAI-1 gene are associated with the risk of stroke and to explore the combined effects of PAI-1 variants and combined oral contraceptive (COC) use for stroke risk. We conducted a nested case-control study using 453 first-ever female stroke cases and 919 age- and region-matched controls that were recruited from our prospective surveillance cohort. SNP rs1799889 was genotyped by allele-specific polymerase chain reaction (PCR), and SNPs rs7242 and rs2227631 were detected by the TaqMan SNP genotyping assay. We identified that rs1799889 5G allele conferred a protective effect against ischemic stroke while 4G allele conferred an increased risk of ischemic stroke. But we failed to suggest associations of rs7242 and rs2227631. COC users had a 1.31-fold (OR=1.31, 95% CI=1.01-1.71) increased risk of stroke compared with the non-users. Furthermore, COC users with rs1799889 4G5G/5G5G genotype had a decreased risk of ischemic stroke (OR=0.53, 95% CI=0.34-0.83). Moreover, haplotype G-5G-T was associated with an increased risk of overall stroke (OR=1.28, 95% CI=1.01-1.62). In contrast, haplotype A-4G-G and haplotype G-5G-T were slightly associated with the protection from ischemic stroke (OR=0.61, 95% CI=0.46-0.82; OR=0.61, 95% CI=0.44-0.85, respectively). The study assessed the associations of three PAI-1 SNPs and also suggested combined effects of these PAI-1 gene variants and COC use on stroke risk in the Han Chinese women.