Abstract Background Common genetic variants in immune and inflammatory response genes can affect the risk of developing oral cancer. Interleukin-10 (IL-10) is an immunosuppressive cytokine which may facilitate development of cancer by supporting tumor escape from the immune response. Inter-individual variations in IL-10 production were genetically contributed to polymorphisms within IL-10 promoter region. We determined whether single nucleotide polymorphisms (SNPs) at positions − 1082 A/G (rs1800870), − 819 T/C (rs1800871) and − 592 A/C (rs1800872) in the IL-10 gene promoter were involved in predisposing an individual to oral cancer. Methods We analyzed 3 SNPS of IL-10 gene promoter in 280 patients with oral cancer and 300 age and sex matched controls in a Chinese population, using a polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) strategy. Results There were significant differences in the genotype and allele distribution of − 1082 A/G (rs1800870) polymorphism of the IL-10 gene among cases and controls. The − 1082 G alleles carriers were associated with a significantly increased risk of oral cancer compared with the non-carriers (OR = 1.821, 95% CI, 1.329–2.496, P < 0.001). Haplotype analysis revealed that the GCC haplotype (defined by SNPs at positions − 1082, − 819 and − 592) of IL-10 gene conveys the highest risk for oral cancer compared with the ATA haplotype (OR = 1.716; 95% CI, 1.230–2.395; P = 0.001). Conclusion IL-10 gene promoter − 1082 A/G (rs1800870) polymorphism, and its haplotype are significantly associated with the risk of oral cancer. Our data suggests that IL-10 gene plays an important role in the development of oral cancer.