The tumor suppressor P53 and its negative regulator mouse double minute 2 (MDM2) play crucial roles in carcinogenesis. Previous case-control studies also revealed that P53 72Arg>Pro and MDM2 309T>G polymorphisms contribute to the risk of common cancers. However, the relationship between these two functional polymorphisms and adult acute lymphoblastic leukemia (ALL) susceptibility has not been explored. In this study, we performed a case-control study to explore the association between MDM2 and P53 gene polymorphisms and ALL risk in a Chinese population. We found an increased adult ALL risk associated with the MDM2 GG (odds ratio [OR]=2.79, 95% confidence interval [95% CI]=1.67-4.68) and TG (OR=1.49, 95% CI=0.95-2.53) genotypes. An increased risk associated with the P53 Pro/Pro genotype (OR=2.22, 95% CI=1.30-3.79) compared with the Arg/Arg genotype was also observed. Furthermore, the gene-gene interaction of MDM2 and P53 polymorphisms increased the adult ALL risk in a super-multiplicative manner (OR for the presence of both MDM2 GG and P53 Pro/Pro genotypes=8.05, 95% CI=2.53-25.58). These findings suggest that polymorphisms of MDM2 and P53 genes may be genetic modifiers for developing adult ALL.