The present study recruited 193 patients with ischemic cerebrovascular disease from Inpatient and Outpatient Departments at the Affiliated Hospital of Qingdao University Medical College, China from August 2008 to May 2010, as well as 120 healthy volunteers from the Medical Examination Center at the Affiliated Hospital of Qingdao University Medical College, China, who served as controls for this study. Patients and control subjects were from the Han population in northern China. Enzyme- linked immunosorbent assay analysis revealed increased levels of serum pregnancy-associated plasma protein-A (PAPP-A) in ischemic cerebrovascular disease patients compared with healthy controls. In addition, the patients exhibited greater frequency of genotype CC and C alleles in a missense A/C (Tyr/Ser) polymorphism (dbSNP: rs7020782) of exon 14 in the PAPP-A gene. Multiple-factor logistic regression analysis on correction of age, gender, history of smoking, hypertension, diabetes mellitus, hypercholesteremia, and ischemic stroke family history showed that the risk for ischemic cerebrovascular disease in the population without the A allele at the A/C genetic locus in exon 14 of the PAPP-A was 2-folds greater than the population expressing the A allele. These experimental findings suggested that ischemic cerebrovascular disease correlated with the C allele in exon 14 of PAPP-A. In addition, the A allele is likely a protective gene; individuals carrying the A allele were less prone to ischemic cerebrovascular disease compared with individuals without the A allele.