Genetic alterations that occur in human breast cancers are believed to be of importance for initiation as well as progression of the disease. In order to find a genetic alteration that may be used as a prognostic marker, 82 familial breast carcinomas were analyzed for loss of constitutional heterozygosity at polymorphic loci on all chromosomes. Frequently occurring allele losses were compared to estrogen receptor expression, lymph node metastases, tumor size at the time of operation, and distant metastases at the time of follow-up 2-15 years later. Loss of heterozygosity (LOH) on the long arm of chromosome 16 in the tumor at the time of operation was significantly correlated (P < 0.001) with the occurrence of distant metastases 1-13 years after the operation. In addition, LOH at 16q was not correlated with estrogen receptor status, lymph node positivity, or tumor size, nor was the occurrence of distant metastases correlated with any of these parameters. The results suggest the existence of a tumor suppressor gene on 16q that facilitates hematogenic spread of breast cancer and that LOH at this locus is an independent prognostic marker in breast cancer.