Objective: Interleukin-10 (IL-10) is a pleiotropic cytokine with either immunosuppressive or immunostimulative activities. It has been reported that in cancer, the promoter region polymorphism of IL-10 (-A592C) alters both the expression and serum levels of this cytokine. In the present study, we have addressed the question as to whether the single nucleotide polymorphisms (SNPs) at positions -592 A/C in the IL-10 gene promoter, could predispose an individual to oral squamous cell carcinoma (OSCC). Design: We analyzed the genotype of the IL-10 (-A592C) gene, in 250 histopathologically confirmed OSCC patients and similar number of healthy volunteers taken as controls, in an Indian population by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Allele and genotype frequencies were analyzed by the Student's t-test and the chi-squared test, and strength of associations by the odds ratio (OR) with 95% confidence intervals. Results: The genotype and allele distribution of IL-10 (-A592C) gene polymorphism was significantly different between OSCC cases and controls (genotype AA vs AC: OR 2.87; 95 % CI 1.50-5.48; p = 0.0016 and AA vs CC: OR 4.08; 95 % CI 1.98-8.41; p = 0.0002). The -592 C alleles were found to be significantly different among OSCC cases and controls (OR: 1.44, 95% CI: 1.12-1.85, p < 0.0051). Conclusions: The IL-10 gene promoter region (-592) A/C polymorphism is significantly associated with reduced risk of OSCC. The OSCC group had a significantly greater frequency of genotype AA as compared to control group. (C) 2017 Elsevier Ltd. All rights reserved.