Morphologic determination of residual plasma cell myeloma is often difficult. This study was conducted to evaluate the diagnostic value of several ancillary methods. A total of 121 bone marrow specimens from patients with myeloma after bone marrow transplantation or chemotherapy were studied. Of those, 49 cases were studied by conventional cytogenetics (CC), 86 by flow cytometry (FC), 50 by immunohistochemical analysis, 72 by molecular studies (MS) for immunoglobulin gene rearrangements, and 18 by standard fluorescence in situ hybridization (FISH) study. Of the patients, 70 were found to have residual myeloma. Residual disease was detected in 58 of 70 patients by morphologic examination (detection rate, 83%), 25 of 26 by immunohistochemical analysis (96%), 39 of 54 by FC (72%), 6 of 40 by CC (15%), 6 of 12 by FISH (50%), and 24 of 40 by MS (60%). Among the ancillary studies, immunohistochemical analysis and FC were the most helpful ancillary studies for detection of residual disease in myeloma, with immunohistochemical analysis the most effective single method.