The oncoprotein MDM4 plays an essential role in P53 tumor suppressor pathway through negative regulation of P53 function. It has been reported that the rs4245739 A > C polymorphism located in the MDM4 3'-untranslated region creates a miR-191 target site and results in decreased MDM4 expression. Therefore, we investigated the association of the MDM4 rs4245739 polymorphism as well as the P53 Arg72Pro genetic variant with the breast cancer risk. Genotypes were determined in two independent case-control sets consisting of 1100 breast cancer cases and 1400 controls from two regions of China. Odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated by logistic regression. Our results demonstrated that the MDM4 rs4245739 AC and CC genotypes were significantly associated with decreased breast cancer risk compared to the AA genotype in both the case-control sets (Jinan set: OR = 0.55, 95 % CI 0.40-0.76, P = 2.3 × 10(-4); Huaian set: OR = 0.41, 95 % CI 0.25-0.67, P = 3.1 × 10(-4)). The P53 Arg/Pro genotype or Pro/Pro genotype was significantly associated with an increased risk of developing breast cancer, compared to the P53 Arg/Arg genotype in both the case-control sets (all P < 0.05). Interestingly, we observed a combinational effect between MDM4 rs4245739 and P53 Arg72Pro variants in attenuating breast cancer risk, highlighting the importance of the P53 tumor suppressor pathway genes during malignant transformation. Our results also support the hypothesis that genetic variants interrupting miRNA-mediated gene regulation might be important genetic modifiers of breast cancer risk.