In light of recently found contribution of factors associated with thrombosis and inflammation to carcinogenesis, we investigated the possible association of coagulation factors XII and XIII with increased risk for oral cancer. In DNA samples of patients with oral squamous cell carcinoma and healthy controls of comparable ethnicity, age and sex, we studied the C46T polymorphism in FXII gene which affects gene transcription and the V34L polymorphism in FXIII gene which affects enzyme activity resulting in alteration of the fibrin network structure. No significant differences were observed in genotype and mutant allele frequencies of the FXII C46T polymorphism between patients and healthy controls. On the contrary, the obtained data for FXIII V34L polymorphism revealed a significant frequency increase of the L allele, which results in thinner fibrin network, in the whole group of patients compared to controls (33.1 versus 22.2% respectively, Fischer value P=0.006). In addition, LL homozygotes had a 3-fold greater risk for developing oral cancer (OR 2.893, 95% CI 1.056-7.890), while in VL heterozygotes a 2-fold greater risk was observed (OR 1.868, 95% CI 1.126-3.101). Significantly increased frequency of L allele was also observed in sub-groups of patients without family history of thrombophilia or cancer, with and without tobacco abuse and with alcohol abuse (P<0.05). Interestingly, in comparison to controls only patients with early cancer stages I and II had significantly increased L alleles and not patients with advanced stages III and IV. These findings suggest that the presence of L allele is strongly associated with oral cancer generation but not with its progression and metastasis. In the presence of L allele, the fibrin network is composed of thinner fibers, is less porous and facilitates tumor stroma formation and therefore tumor cell proliferation. Nevertheless, this thinner and less porous fibrin network inhibits cell migration.