The histogenesis of carcinosarcomas is controversial, specifically with respect to clonality and cell of origin. To answer these questions, tumor cells from both epithelial and spindle-cell components were microdissected from three cases each of mammary carcinosarcoma and its postulated precursor, carcinoma with spindle-cell metaplasia. Clonality was assessed using the principle of X chromosome inactivation. Loss of heterozygosity (LOH) was evaluated at seven chromosomal loci to assess shared and distinctive genetic alterations for the two components in each tumor. All of the six cases demonstrated identical clonality of the carcinomatous and spindle-cell components, identical to a focus of ductal carcinoma in situ present in one case. LOH for NM23 was detected in both components in one carcinosarcoma, whereas LOH for INT-2 was detected in both components in one metaplastic carcinoma. Differential LOH for D11S904 was present in only the mesenchymal components of these two cases. We conclude that the two components of carcinosarcoma and its precursor are clonal and that the sarcomatous and spindle-cell components arise from mutation of the carcinoma. Presence of differential LOH at D11S904 in only the spindle-cell components suggests that this mutation might be critical to the development of this second phenotype.