Genetic background plays an important role in susceptibility to ischemic stroke. Our aim was to investigate the association of genetic polymorphisms and ischemic stroke and to evaluate their interaction with environmental risk factors in the Chinese population. Angiotensin-converting enzyme (ACE) gene I/D polymorphism, apolipoprotein E (ApoE) gene polymorphism, methylenetetrahydrofolate reductase (MTHFR) gene 677C/T polymorphism, and beta fibrinogen (Fgbeta) gene 148C/T polymorphism were analyzed in 100 patients and 100 matched controls. The subjects were genotyped by polymerase chain reaction (PCR) amplification and denaturing high-performance liquid chromatography (DHPLC) analysis. Persons with the Fgbeta CT/TT, MTHFR CT/TT, and ACE ID/DD genotypes had an elevated incidence of ischemic stroke (OR 3.907, 95% CI, 1.160-13.162, P=0.028). Smokers with the Fgbeta CT/TT or APOEepsilon4epsilon3 genotype, as well as individuals with the Fgbeta CT/TT genotype who consumed alcohol were more likely to develop a stroke. The data indicate that certain unfavorable genotypic combinations act synergistically in the development of ischemic stroke in the Chinese population. Synergism was also observed between genotype and environmental risk factors. This study may facilitate the development of a strategy to effectively prevent ischemic strokes.