Growing evidence suggests that interleukin-18 (IL-18) levels may affect neoplasia and that single nucleotide polymorphisms (SNPs) within IL-18 gene may influence its production. In this study, we evaluated whether IL-18 and IL-18 receptor (IL-18R) polymorphisms are associated with the development and clinicopathological features of papillary thyroid carcinoma (PTC). Using direct sequencing, we investigated the association between functional polymorphisms of IL-18 and IL-18R genes and susceptibility to PTC in 94 PTC patients and 260 healthy controls. Genetic data were analyzed using commercially available software. Multiple logistic regression models were used to calculate odds ratios, 95% confidence intervals, and P-values for the association between the genotypes and risk of PTC. The PTC patients were further subgrouped and compared with respect to their clinicopathological characteristics. 3 SNPs of IL-18 (rs549908, rs360717, and rs187238) and one of IL-18R (rs1420106) examined in this study were significantly associated with the development of PTC. The allelic frequencies of the 3 SNPs of IL-18 also showed significant association with lymph node metastasis. IL-18 and IL-18R polymorphisms may contribute to the development and lymph node metastasis of PTC.