Objective:To investigate the association of two functional single nucleotide polymorphisms in the promoter region of the interleukin-18 gene, at positions −607 and −137, with head and neck squamous cell carcinoma.Design:Genomic deoxyribonucleic acid was extracted, by the salting-out method, from peripheral blood leukocytes. Single nucleotide polymorphisms of the interleukin-18 gene at positions −607 (cytosine/adenine) and −137 (guanine/cytosine) were analysed by sequence-specific polymerase chain reaction.Subjects:One hundred and eleven patients (86 men and 25 women; mean age 56.7±13.7 years) and 212 regional controls (165 men and 47 women; mean age 53.3±12.2 years) were studied. Control subjects comprised healthy volunteers or cancer-free individuals presenting with otolaryngological disease. The diagnosis of squamous cell carcinoma was confirmed histopathologically. Various clinical parameters were collected at diagnosis, including tumour site, tumour size, lymph node involvement, distant metastasis and stage.Results:There was no significant association between the allele, genotype or haplotype frequencies of the two single nucleotide polymorphisms of the interleukin-18 promoter and the head and neck squamous cell carcinoma susceptibility or clinical parameters at diagnosis.Conclusion:Interleukin-18 polymorphisms at positions −607 and −137 did not confer susceptibility to head and neck squamous cell carcinoma in southern Iranian patients.