Introduction: It has been shown that the host immune response and chronic inflammation could play a role as important risk factors for cancer. Oral squamous cell carcinoma (OSCC) is a common cancer worldwide. In this study, we aimed to evaluate the impact of interleukin-1 receptor antagonist (IL-1RA) and IL-4 variable number tandem repeat (VNTR) polymorphisms on OSCC susceptibility in a Turkish population. Methods: Study subjects comprised of 36 OSCC patients and 100 healthy controls. Genotyping of the IL-1RA VNTR (rs2234663) and IL-4 VNTR (rs79071878) polymorphisms were analyzed by polymerase chain reaction. Results: The frequency of IL-1RA VNTR 1/2+2/2 genotypes increased in the patients than healthy controls while IL-1RA VNTR 1/1 genotype was higher in the control group than in the patients (p=0.002). The subjects carrying IL-1RA VNTR 1/2+2/2 genotypes showed a 12.011-fold increased risk of susceptibility to OSCC. IL-1RA VNTR allele 1 was higher in the control group than the patient group while IL-1RA VNTR allele 2 was higher in the patient group than the control group (respectively, p=0.000, p=0.000). The subjects carrying IL-1RA VNTR allele 2 showed a 2.609-fold increased risk of susceptibility to OSCC. The IL-4 VNTR P1/P1 and P1/P2 genotype frequencies were higher in the patient group compared to the control group (p=0.039). IL-4 VNTR P1 allele was higher in the patients compared to the controls (p=0.030). Conclusion: The significant association between the functional VNTR polymorphisms of IL-1RA/IL-4 genes and OSCC suspectibility in a Turkish population confirmed a role of altered inflammatory process in OSCC pathogenesis.