Size changes in microsatellite sequences have been detected in many types of cancer, but the influence of this form of genetic instability on disease progression remains unclear. We determined the incidence of microsatellite instability in breast cancer by comparing PCR-amplified sequences from paraffin-embedded samples of normal and tumor tissue from affected individuals. This analysis showed that at least 30% of breast cancers exhibit microsatellite instability (MI). Of importance, MI correlated with indicators commonly associated with poor disease prognosis, including lymph node status, tumor size, and advanced tumor stage. Individuals with MI+ tumors also showed significantly reduced disease-free and overall survival. These data contrast with studies showing that MI correlates with improved prognosis in colon and gastric cancers. We propose that defects resulting in MI promote disease progression and result in a poor prognosis in breast cancer.