CONTEXT: Tumors with mixed morphologic patterns (combined tumors) are sometimes encountered, and questions often arise regarding the mechanism of molecular pathogenesis of each component and their relationships. OBJECTIVE: To determine whether different components of combined tumors contain the same or different genetic alterations, thus providing evidence for their clonality. MATERIALS AND METHODS: Six combined tumors with 2 components (in each case, both components showed epithelial differentiation morphologically) were studied by microdissecting tumor cells from each morphologic area followed by loss of heterozygosity analysis. RESULTS: In 1 of the cases studied, the different morphologic areas contained different patterns of genetic alterations. In the remaining 5 cases, the different morphologic areas harbored identical genetic changes in the chromosome regions studied. The latter group, interestingly, included a colonic tumor with an area of tubulovillous adenoma and an area of neuroendocrine carcinoma, and 2 lung tumors with squamous carcinoma and small cell carcinoma components. CONCLUSIONS: Our results suggest that in the majority of combined tumors, cells with different phenotypes share similar genotype and may arise from a single precursor cell. However, in a minority of these tumors, different areas may be derived from different precursor cells.