To investigate whether the 4G/5G polymorphism of plasminogen activator inhibitor type 1 (PAI-1) and the -7351 C/T polymorphism of tissue-type plasminogen activator (t-PA) are associated with ischemic stroke, we conducted a case-control study of 190 hospital cases of first-ever ischemic stroke and 185 community-based controls. Our findings do not indicate any association between the PAI-1 or t-PA polymorphisms and risk of stroke. Adding our PAI-1 results to previous studies in a meta-analysis indicated a strong association between this polymorphism and ischemic stroke (P = .0002), with no publication bias but with extreme heterogeneity. There was evidence of stroke association with the PAI-1 4G/5G locus. Strong heterogeneity indicates the need to address other issues, including association with particular stroke subtypes or linkage disequilibrium (LD) with another causative allele. The results also sound a cautionary note that varying LD structure across populations may obscure the relationship with a causative locus, and that future meta-analyses need to look beyond a simple pooled estimate.