Previous studies have suggested that a decreased fibrinolytic potential can play a role as risk factor for thrombotic events. Blood levels of factors of the fibrinolytic system are highly heritable, supporting the importance of the genetic background. To better understand the impact of two common polymorphisms of the tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) genes on the in vivo regulation of fibrinolysis, we have studied this genetic variables together with other clinical and metabolic factors in a sample of the Italian population. Two hundred-eighteen subjects without history of atherothrombosis or mayor diseases entered the study. A detailed clinical history was collected and evaluations of blood levels of cholesterol, triglycerides, PAI-1 activity, PAI-1 antigen, t-PA activity, t-PA antigen were performed on standard conditions. Genotypes at the locus of the 4G/5G polymorphism of PAI-1 gene promoter and at locus of the insertion/deletion Alu-repeat polymorphism of t-PA gene intron h were studied. No detectable effect was found for the t-PA gene polymorphism in our population. On the other hand, the 4G/5G polymorphism was found to modulate plasma PAI-1 activity levels and the interaction between PAI-1 plasma activity levels and blood lipids. Moreover, such regulation by genotype was found to be affected by the presence or absence of dyslipidemia. In conclusion, our findings suggest that, among subjects with or without metabolic disorders such as dyslipidemia, completely different gene-environment interactions may occur, and could affect the individual risk of thrombosis.