Previous studies suggest that osteopontin (OPN) levels are associated with the incidence and development of multiple types of cancer. This study analyzes the correlation between OPN gene variants and nasopharyngeal carcinoma (NPC). A total of 150 NPC patients and 150 healthy adults were enrolled and divided into NPC and control groups. In both groups, four OPN polymorphisms including rs1126772, rs4754, rs11728697 and rs9138 were quantitatively genotyped by SNaPshot SNP genotyping assay. Allele frequencies of four OPN polymorphisms were compared between two groups. No statistical significance was noted regarding genotype frequency of four OPN polymorphisms between male NPC and healthy subjects (all P > 0.05). Female subjects between two groups significantly differed in terms of genotype frequency of rs1172869 (P = 0.002). No statistical significance was observed in allele frequencies in each of four OPN polymorphisms between two groups (all P > 0.05). For NPC patients, the polymorphisms information content (PIC) ranged from 0.2961 to 0.3584 and 0.3047 to 0.3655 for normal controls. Additionally, rs11728697 had the highest effective number of alleles (Ne), expected heterozygosity (HE) and PIC in two groups. Female subjects in two groups significantly differed in the genotype frequency of rs1172869 while no statistical significance was noted for male counterparts. All subjects in the NPC and control groups had similar allele frequency. All the four OPN polymorphisms were moderately polymorphic. The mean NA, Ne, Ho, He and PIC of each OPN polymorphism in the control group were higher than those in the NPC group without a significant difference.