Germline mutations at BRCA1 or BRCA2 genes result in susceptibility to breast and ovarian cancers. BRCA1- and BRCA2-associated tumors have distinct histologic and molecular phenotypes, as compared to sporadic breast tumors. Typically, a higher grade of malignancy is observed in BRCA-associated cancers. A number of studies have suggested that BRCA1 and BRCA2 proteins are of importance in DNA repair and maintenance of genome integrity, bringing about molecular models of tumor pathogenesis. In particular, alterations at p53 gene have been suggested to be a necessary step in the tumorigenesis of BRCA-associated carcinomas. In fact, BRCA-associated breast cancers have higher p53 mutation frequencies than sporadic ones. At present, very little is known regarding BRCA non-associated familial tumors (termed BRCAx tumors). To our knowledge no data is available on p53 alterations in this sub-group of familial tumors. In this study p53 alteration frequencies were evaluated in 13 BRCA1, 11 BRCA2 and 55 BRCAx breast tumors. Tumor samples were analyzed for p53 gene mutations by PCR-SSCP/direct sequencing, and for p53 protein overexpression by immunohistochemistry (IHC). Altogether, p53 alterations were detected in 54% of BRCAI tumors compared with 5% of BRCAx tumors. No p53 alteration was found in BRCA2 tumors. While loss of p53 checkpoint control is likely to be an important step in the molecular pathogenesis of BRCA1-associated cancers, our data seem to indicate a p53-independent molecular mechanism underlying BRCAx neoplastic transformation.