The BRCA1 and BRCA2 genes are involved in genetic susceptibility to breast cancer (BC). Nevertheless, in a relevant number of families displaying a disease pattern suggesting an inherited susceptibility to BC, mutational analysis fails to detect any defect in the BRCA genes. Therefore, women belonging to such families should be considered eligible for programs aimed at BC control in individuals at hereditary risk. A clinico-mammographic surveillance program for women at high genetic risk, as defined on the basis of pedigree, has been carried out at our centre for ten years, leading to the diagnosis of 19 new BC cases. Only in 13% of the families analysed, the underlying genetic defect was evidenced in BRCA1 or 2. Here we describe two BC prone families where, although no mutations were detected in BRCA genes, follow-up confirmed an increased BC incidence. In three women belonging to these families clinico-mammographic surveillance resulted to be successful in detecting early-stage BC, supporting the usefulness of screening women from high-risk families, irrespective of whether a mutation was found.