Abstract: Objective To investigate the association of the genetic polymorphisms rs2255393 and rs968998 in Nogo gene with the susceptibility of nasopharyngeal carcinoma (NPC). Methods SNaPshot and DNA sequencing were used to screen the genotypes of rs2255393 and rs968998 in 276 NPC patients and 276 healthy volunteers. The comparison of distribution differences of genotype and allele frequencies was performed using statistical methods in disease and control groups. Results The difference of genotype and allele frequencies in rs968998 between NPC patients and controls had no statistical significance (all P>0.05). However, the difference between TT genotype (OR=0.58, 95% CI:0.34-0.97, P=0.039) and dominant model (AA+TA) of rs2255393 (OR=0.62, 95% CI:0.44-0.87, P=0.006) was statistically significant in NPC patients and controls. Moreover, The frequencies of its T allele in NPC patients was lower than those in controls, and the distribution difference was statistically significant (OR=0.72, 95% CI:0.56-0.92, P=0.009). There was no statistically significant difference between rs2255393 polymorphism and NPC pathological features (clinical staging, lymphatic metastasis and distant metastasis) (all P>0.05). Conclusions The genetic polymorphism rs2255393 of Nogo gene is associated with the risk of nasopharyngeal carcinoma, but is not correlated with clinical tumor staging.