Chronic venous insufficiency (CVI) is a common disease associated with poor quality of life. Genetic polymorphisms causing coagulation abnormalities may account for some of the CVI pathogenesis. Type I plasminogen activator inhibitor (PAI-1) is responsible for fibrinolytic system regulation, and plasma levels of PAI-1 are strongly correlated with PAI-1 4G/5G gene polymorphism. The association between PAI-1 4G/5G gene polymorphism and CVI was investigated. In 34 consecutive patients with clinically overt CVI, the PAI-1 4G/4G polymorphism was detected in three cases (8.8%); the 4G/5G polymorphism was detected in 28 (82.4%). In 34 age- and sex-matched controls, the PAI-1 4G/4G polymorphism was detected in one case (2.9%) and the 4G/5G polymorphism was detected in 14 cases (41.2%). The PAI-1 4G allele was found significantly more frequently in CVI patients than in controls. The 4G allele was associated with a 3.25-fold increase in CVI risk. Thus, a relationship between CVI and the PAI-1 4G allele is apparent.