Replication errors (RER) at microsatellite repeats indicate genomic instability in hereditary nonpolyposis colorectal cancer (HNPCC) and in some sporadic cancers. We have studied genomic instability in 313 sporadic breast tumors and in 106 tumors from BRCA2, 999del5 carriers at 43 genomic loci on 13 chromosomes. RER was observed in 8/419 (1.9%) of the cases at one or more chromosomal loci. The frequencies of type I and type II RER were similar. The majority of RER+ tumors showed ER+, PgR+, high S-phase fraction, tumor size >2 cm and LOH at 2p, 2q and 3p. All 8 RER+ tumors were of the ductal histotype. The breast cancer cases with RER are not part of an HNPCC syndrome and a family history of colorectal cancer growth is not detected in relatives, with the exception of one case. However, four of the RER+ cases are from individuals carrying the BRCA2, 999del5 mutation. We conclude that RER is a rare somatic event during human breast carcinogenesis and may be associated with progression of breast carcinomas.