The relationship between ductal and lobular breast carcinoma is highlighted in cases in which these morphologically divergent carcinomas coexist in proximity within a single patient. We hypothesized that such cases may result from the proliferation of a precursor lesion into a tumor containing areas of divergent morphologic features. In this study, we analyzed loss of heterozygosity (LOH) in 10 cases of coexistent ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS), and invasive carcinoma. DNA from the separate components of each lesion was subjected to LOH analysis using 13 markers on 7 chromosomes. In 7 cases, the DCIS and LCIS shared loss of a common allele, suggesting a clonal relationship. The invasive component shared loss of the same allele in 5 tumors. This finding indicates that coexistent lobular and ductal carcinomas exhibit shared genetic abnormalities, contradicting the conventional concept that these lesions represent separate, exclusive pathways of breast neoplasia. Instead, these traditionally segregated classes of breast cancer may, in fact, share common precursor lesions.