Interleukin (IL)-18, a proinflammatory cytokine, induces T-helper 1 differentiation and cytotoxic T-lymphocyte functions, both of which have been proposed in the pathogenesis of oral lichen planus (OLP) - an oral disease resembles oral mucosal graft-versus-host disease (GVHD) both clinically and histologically. The aim of this study was to evaluate the association of single nucleotide polymorphisms (SNPs) in the IL18 gene on the chromosome 11q22 in patients with OLP. Four SNPs of the IL18 gene at positions -137G/C (rs187238), -607C/A (rs1946518), -656G/T (rs1946519), and 1248A/G (rs189667) were analyzed in 151 patients with OLP and 143 normal controls using polymerase chain reaction-sequence-specific primers method, and the serum level of IL-18 protein was determined by enzyme-linked immunosorbent assay (ELISA). The data revealed that there is a significant difference in IL18-607 genotype distributions between the patient group and the control group (P < 0.001), and the polymorphism -137G/C also appears to be statistically associated with the more severe erosive subtype (eOLP) (P = 0.023). The identified polymorphisms at the IL-18 promoter region (i.e. -137GG) are likely to exert positive effect on the production of IL-18 protein in OLP, as detected by ELISA. Using phase software, four haplotypes were deduced from the two polymorphisms -607C/A and -137G/C, named haplotypes I to IV, and the haplotypes I, II, and IV are significantly associated with OLP (P < 0.001). Our data suggest that the identified IL18 polymorphisms may be associated with the pathogenesis of OLP in this Chinese cohort by upregulation of IL-18 production in vivo.