The aim of this study was to determine the association of the microRNA-146a (miR-146a) polymorphism with the risk of diffuse large B cell lymphoma (DLBCL). The genotyping of miR-146a rs2910164 polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results showed that CC genotype and C alleles distribution in the DLBCL patient was significantly higher than that of the controls (p = 0.01 and p = 0.01, respectively). No significant differences were found between the two subgroups when stratified by clinical characteristics including sexual, age at admission, performance status, pathological type, Ann Arbor stage, LDH and β2-MG value. The miR-146a expression was detected by the Taqman real-time PCR. The result showed that the miR-146a expression was notably upregulated in DLBCL patients when compared with controls (p = 0.02). In addition, the miR-146a expression of CC genotypes subgroup was drastically downregulated than that of GC/GG genotype subgroup in DLBCL patients (p = 0.0003), suggesting that this polymorphism can functionally affect the expression of miR-146a. In conclusion, it was shown that the miR-146a rs2910164 polymorphism is associated with the risk of DLBCL in the Chinese Han population.