p73 gene shares structural and functional similarities to p53, and plays an important role in modulating cell-cycle arrest and apoptosis. A common non-coding polymorphism of exon 2 of the p73 gene (designated as GC/AT) may affect gene expression, thus, it may lead to functional significance. The correlation of this polymorphism with breast cancer survival has not been investigated. In this study, by using genomic DNA p73 GC/AT polymorphism was detected by PCR-SSCP in 526 breast cancer patients with a median follow-up of 7.3 years. Among the 526 breast cancer patients, 4% of the patients were homozygous for the AT/AT genotype, 39% were heterozygous GC/AT and 57% were homozygous for the GC/GC genotype. We found that patients with the GC/GC genotype had a significantly worse clinical outcome than did patients with the AT Variants (AT/AT or GC/AT genotype) (5-year disease-free survival, 74.2 versus 95.0 or 84.1%, P=0.02; 5-year overall survival, 78.9 versus 95.0 or 87.5%, P=0.01, respectively). As compared with the GC/AT and AT/AT genotypes, the GC/GC genotype remained an independent prognostic indicator of disease-free survival (HR 1.82, P=0.003) and overall survival (HR 1.99, P=0.004) in multivariate analysis. Our results suggest that the GC/GC genotype is significantly associated with poor prognosis in breast cancer and raise the possibility that analysis of p73 polymorphism may provide useful prognostic information for breast cancer patients. Additional independent studies are needed to confirm these findings.