BACKGROUND: Polymorphisms in genes encoding tumor necrosis factor-alpha (TNF-alpha) and its receptor TNF-R1 have been shown to affect one person's susceptibility to develop certain neoplastic diseases. The aim of the present association study was to investigate whether single nucleotide polymorphisms (SNPs) in TNF-alpha (-308G>A) and TNF-R1 (36A>G) genes modulate the susceptibility for keratocystic odontogenic tumors (KCOTs) development in Serbian patients. METHODS: Genotyping was performed in 60 KCOT patients and 125 healthy individuals, using polymerase chain reaction/restriction fragment length polymorphism analysis. RESULTS: A significant difference in genotype and allele frequencies was found between patients and controls for both SNPs (P < 0.05). Carriers of the TNF-alpha A variant had an eightfold increase of KCOT risk (OR = 8.12, 95% CI = 3.98-16.56, P < 0.0001), while carriers of the TNF-R1 G variant had approximately a fourfold increase of KCOT risk (OR= 3.65, CI: 1.60-8.40, P = 0.001). CONCLUSIONS: Our findings suggest that the two polymorphisms are strong risk factors for KCOT development in Serbian population.