The aim of this study was to explore potential relationships of four single-nucleotide polymorphisms (SNPs) in the gene encoding dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) with risk of nasopharyngeal carcinoma (NPC). The DC-SIGN SNPs rs7252229, rs4804803, rs2287886, and rs735240 were genotyped in 477 unrelated NPC patients and 561 cancer-free controls. At rs7252229, risk of NPC was significantly lower in individuals with GC (odds ratio [OR] 0.076, 95% confidence interval [CI] 0.008-0.690), GG (OR 0.056, 95%CI 0.006-0.487), or GC + GG (OR 0.059, 95%CI 0.007-0.515) than in individuals with the CC genotype, after adjusting for age, gender, smoking history, and EBV-VCA-IgA status. At rs4804803, risk of NPC was significantly higher in individuals with the genotype GG than in those with the genotype AA (adjusted OR 9.038, 95%CI 1.708-47.822). At rs735240, risk of NPC did not change significantly with genotypes AG, GG, or AG + GG after adjusting for age, gender, and smoking history. However, when data were also adjusted for EBV-VCA-IgA status, three genotypes emerged as associated with significantly higher risk of NPC than the AA genotype: AG (OR 2.976, 95%CI 1.123-7.888), GG (OR 3.314, 95%CI 1.274-8.622), or GG + AG (OR 3.191, 95%CI 1.237-8.230). Our results suggest that DC-SIGN SNPs rs7252229, rs4804803, and rs735240 may influence NPC risk in the Chinese population. The mechanisms mediating this risk require a further study.