Nasopharyngeal carcinoma (NPC) is one of the most common cancers in southern China. In addition to environmental factors such as Epstein-Barr virus infection and chemical carcinogen exposure, genetic susceptibility has been reported to play a key role in the development of this disease. Interleukin-18 (IL-18) is a multifunctional cytokine that induces interferon-gamma secretion and plays an important role in antitumor immunity. Variations in the DNA sequence of the IL-18 gene promoter may lead to altered IL-18 production and/or activity, so this can modulate an individual's susceptibility to NPC. To test this hypothesis, we analyzed two single-nucleotide polymorphisms of IL-18 gene promoter, -137 G/C and -607 C/A, in 250 patients with NPC and 270 age- and sex-matched controls, using polymerase chain reaction-restriction fragment length polymorphism. Two polymorphisms, -137 G/C and -607 C/A, were in strong linkage disequilibrium. There were significant differences in the genotype and allele distribution of -137 G/C polymorphism of the IL-18 gene among cases and controls. The -137 GC and CC genotypes were associated with a significantly increased risk of NPC as compared with the -137 GG genotypes (odds ratio [OR] = 1.697; 95% confidence interval [CI], 1.158-2.488; p = 0.007, and OR = 2.700; 95% CI, 1.268-5.751; p = 0.008, respectively). Consistent with the results of the genotyping analyses, the -137 C/-607 A haplotype was associated with a significantly increased risk of NPC as compared with the -137 G/-607 C haplotype (OR = 1.721; 95% CI, 1.262-2.349; p = 0.001).