The allelic variant MDM2-SNP309 (T>G) has been suggested to influence cancer development, but the clinical correlation between the risk allele and breast cancer remains controversial. The genetic background and the ethnicity of selected subgroups may influence the power of these risk genotypes. In this study, we investigated whether MDM2-SNP309 is associated with p53 R72P genetic polymorphism for the risk of breast cancer development in Asian Taiwanese, which has not been well-studied in this regard. Two hundred and fifty-five patients and 324 cancer-free controls were included, and we found that the MDM2-SNP309 TG and GG genotypes displayed marginally increased risks of breast cancer (GG vs. TT: OR = 1.7, 95% CI = 0.93 to 3.09; TG + TT vs. TT: OR = 1.57, 95% CI = 0.98 to 2.56). The breast cancer risk associated with MDM2-SNP309 was enhanced after stratification for the homozygous GG genotype at p53 codon 72 representing the Arg form of this genotype (GG vs. TT: OR = 3.7, 95% CI = 1.144 to 12.02; TG + GG vs. TT: OR = 2.7, 95% CI = 1.027 to 6.895). Also, the median age at diagnosis of patients with MDM2-SNP309 GG increased from 4 years earlier to 9 years earlier than TT patients after stratification for the GG genotype at p53 codon 72. Moreover, the G-allele of MDM2-SNP309 exhibited a stronger capacity than the T-allele to drive the full-length P2 promoter of the MDM2 gene in several human cell lines, suggesting that the association between MDM2-SNP309 and breast cancer is likely multifactorial rather than due to inconsistent gene expression in different cancer sources.