Background: Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI- 1) are involved in the pathogenesis of periodontitis by controlling proteolytic events in the extracellular matrix. This study was designed to investigate the association of t-PA and PAI-1 gene polymorphisms with chronic periodontitis (CP). Methods: One hundred eighty-nine subjects were included. Genomic DNA was obtained from the peripheral blood of 84 patients with CP and 105 periodontally healthy subjects. Polymerase chain reaction and endonuclease digestion was used to genotype the 4G/5G polymorphism in the promoter region of the PAI-1 gene and the Alu-repeat insertion (I)/deletion (D) polymorphism in intron 8 of the t-PA gene. Results: The genotype distributions and allele frequencies of t-PA polymorphism were not different between patients with CP and healthy subjects (24.7% I/I, 45.7% I/D, and 29.6% D/D and 30.3% I/I, 45.5% I/D, and 24.2% D/D, respectively; P >0.05). The t-PA D allele frequency was similar in patients with CP (52.4%) and healthy subjects (46.5%). PAI-1 genotype distribution in patients with CP (30.9% 4G/4G, 35.8% 4G/5G, and 33.3% 5G/5G) and healthy subjects (36.2% 4G/4G, 41.9% 4G/5G, and 21.9% 5G/5G) was also similar. The 4G allele frequency was not different between patients with CP (48.8%) and healthy subjects (57. 1 %) (P >0.05). The 4G allele frequency in non-smoking CP patients was significantly lower than in non-smoking, healthy subjects (X-2 = 4.201; P = 0.040). Non-smoking CP patients also had a significantly lower percentage of 4G-positive genotypes compared to non-smoking healthy subjects (X-2 = 5.046; P= 0.025). Conclusions: t-PA or PAI-1 genotypes are not associated with susceptibility to CP in Turkish subjects. Conversely, the 4G allele of the PAI-1 gene could be related to a decreased susceptibility to CP in non-smokers.