Mutations in the p53 gene were detected in 58% of tumor DNAs of patients with a family history of breast cancer (FHBC) compared to 13% with sporadic breast cancer. Seven of 18 FHBC tumors contained the same G to C transversion in codon 156. Novel alleles of altered length were seen in one or more loci on chromosome 17 in 15 of 18 patients with FHBC but only in a single locus in 8 of 14 patients with sporadic breast cancer. The frequency of tumors with mutations in p53, often multiple, accompanied by the appearance of multiple altered-length alleles suggest that DNA replication or repair defects may presage genomic instability in cases with FHBC.