Nasopharyngeal carcinoma (NPC) is multifactorial, and the genetic background may be a crucial etiologic factor. Interleukin-12 (IL-12) is a multifunctional cytokine that induces interferon (IFN)-gamma secretion and plays an important role in antitumor immunity. Interleukin-27 (IL-27) is a novel IL-12 family member, the present studies demonstrate that IL-27 mediates potent antitumor activity. Variations in the DNA sequence in the IL-12 and IL-27 gene may lead to altered cytokines production and/or activity, and so this can modulate an individual's susceptibility to NPC. To test this hypothesis, we investigated the relationship of IL-12 and IL-27 gene polymorphisms and NPC in a Chinese population. We analyzed single nucleotide polymorphisms (SNPs) of IL-12 gene 16974 A/C and IL-27 gene -964 A/G, 2905 T/G, 4730 T/C in 302 patients with NPC and 310 age- and sex-matched controls, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing methods. There were significant differences in the genotype and allele distribution of 16974 A/C polymorphism of the IL-12 gene among cases and controls. The 16974 CC and AC genotypes were associated with a significantly increased risk of NPC as compared with the 16974 AA genotypes (OR = 2.225, 95% CI 1.395-3.549, P = 0.001 and OR = 1.834, 95% CI 1.239-2.716, P = 0.002, respectively). The 16974 C allele was associated with a significantly increased risk of NPC as compared with the 16974 A allele (OR = 1.334, 95% CI 1.065-1.670, P = 0.012). However, genotype and allele frequencies of the IL-27 gene -964 A/G, 2905 T/G, 4730 T/C polymorphisms in NPC patients were not significantly different than that in healthy controls (P > 0.05). Our data suggest that IL-12 gene may play a role in the development of NPC.