Because of the relative insensitivity of conventional cytogenetics for identifying abnormalities in the non-chronic myelogenous leukemia (CML) myeloproliferative disorders (MPDs), we directly compared the abilities of flow cytometry and cytogenetics to identify such cases. We retrospectively identified 66 patients whose bone marrow samples were evaluated for abnormalities of myeloid antigen expression by 4-color flow cytometry as part of the workup to rule out a non-CML MPD. The patients all had concurrent cytogenetic evaluation of the marrow and no evidence of the t(9;22). Compared with a series of 12 normal bone marrow samples, 30 of 66 specimens demonstrated definitive flow cytometric abnormalities, while the other 36 cases had normal (21 cases) or indeterminate (15 cases) results, with the latter showing only mild antigenic alterations. Strikingly, clonal cytogenetic abnormalities were found in 11 (37%) of the 30 cases with flow cytometric abnormalities, compared with no cytogenetic abnormalities among the 36 normal and indeterminate cases. The most common abnormal myeloid-associated antigens included HLA-DR, CD13, and CD33. In experienced laboratories, 4-color flow cytometry represents a useful method to help distinguish benign from neoplastic marrow in the workup of non-CML MPDs.