Background and Purpose -The tissue-type plasminogen activator (tPA) -7351C > T and the plasminogen activator inhibitor type 1 (PAI-1) -675 4G >5G polymorphisms influence transcriptional activity. Both variants have been associated with myocardial infarction, with increased risk for the T and 4G allele, respectively. In this study we investigated the possible association between these polymorphisms, the respective plasma protein levels, and ischemic stroke. Methods -In the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), 600 patients with acute ischemic stroke aged 18 to 69 years and 600 matched community controls were recruited. Stroke subtype was determined using Trial of Org 10172 in Acute Trea tment criteria. Results -There were no associations between individual genetic variants and ischemic stroke. The multivariate-adjusted odds ratio for overall ischemic stroke was 1.11 (95%CI 0.87 to 1.43) for tPA T allele carriers, and 0. 84 (95%CI, 0.64 to 1.11) for subjects homozygous for the PAI-1 4G allele. When genotypes were combined, a protective effect for the tPA CC/PAI-1 4G4G genotyp e combination was observed (odds ratio 0.65, 95%CI 0.43 to 0.98; P < 0.05). Pla sma levels of tPA and PAI-1 antigen at follow-up were independently associated with overall ischemic stroke. tPA-antigen differed by stroke subtype and was h ighest among those with large-vessel disease and cardioembolic stroke. Conclusi ons -Neither the tPA -7351C > T nor the PAI-1 to 675 4G >5G polymorphism show ed significant association with ischemic stroke. For the tPA CC/PAI-1 4G4G geno type combination, a protective effect was observed. Collectively, these results are consistent with a more complex role for tPA and PAI-1 in the brain as compa red with the heart. Background and Purpose -The tissue-type plasminogen activator (tPA) -7351C> T and the plasminogen activator inhibitor type 1 (PAI-1) -675 4G> 5G polymorphisms influence transcriptional activity. Both variants have been associated with myocardial infarction, with increased risk for the T and 4G allele, respectively. In this study we investigated the possible association between these polymorphisms, the respective plasma protein levels, and ischemic stroke. Methods-In the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), 600 patients with acute ischemic stroke aged 18 to 69 years and 600 matched community controls were recruited. Stroke subtype was determined using Trial of Org 10172 in Acute Trea tment criteria. Results -There were no associations between individual genetic variants and ischemic stroke. The multivariate-adjusted odds ratio for systemic ischemic stroke was 1.11 (95% CI 0.87 to 1.43) for tPA T allele carriers, and 0.84 (95% CI, 0.64 to 1.11) for subjects homozygous for the PAI-1 4G allele. When genotypes were combined, a protective effect for the tPA CC / PAI-1 4G4G genotypic combination was observed (odds ratio 0.65, 95% CI 0.43 to 0.98; P <0.05) of tPA and PAI-1 antigen at follow-up were independently associated with overall ischemic stroke. tPA-antigen differed by stroke subtype and was h ighest among those with large-vessel disease and cardioembolic stroke. Conclusi ons - Negative the tPA -7351C> T nor the PAI-1 to 675 4G> 5G polymorphism show ed significant association with ischemic stroke. For the tPA CC / PAI-1 4G4G geno type combination, a protective effect was observed. Collectively, these results are consistent with a more complex role for tPA and PAI-1 in the brain as compa red with the heart.