Several different investigations and methodologies have provided data supporting a monoclonal origin of neoplasia. For example, the vast majority of neoplastic disorders are cytogenetically monoclonal. Occasionally, however, clones with unrelated karyotypic anomalies are found, as, for example, in approximately 2% of acute myeloid leukemias (AML), myelodysplastic syndromes (MDS), and chronic myeloproliferative disorders (CMD). Whether such a cytogenetic polyclonality represents a polyclonal origin or whether different clones share a submicroscopic primary change, indicating a monoclonal origin, remains to be elucidated. Our objective was to ascertain if cryptic aberrations can be found in cytogenetically polyclonal hematologic malignancies using multicolor fluorescence in situ hybridization (M-FISH). Fourteen AML, MDS, and CMD cases were investigated. In none of these was a cryptic aberration found, common to all subclones, although the karyotypes were revised in two AMLs and one MDS. Thus, all malignancies were still classified as polyclonal after the M-FISH analyses. Based on the present results, we conclude that M-FISH, in general, does not reveal primary cryptic aberrations supporting a monoclonal origin of cytogenetically polyclonal hematologic malignancies.