Although 70% to 80% of plasma cell myelomas (PCMs) express CD56, few data are available on the usefulness of CD56 immunohistochemical analysis in assessing residual disease. We retrospectively reviewed 127 PCM posttreatment bone marrow (BM) specimens, classifying them as positive or negative for residual disease (independent of CD56 immunohistochemical studies) based on abnormal plasma cell (PC) morphologic features or flow cytometry (FC) and/or light chain restriction by immunohistochemical studies (conventional criteria). CD56 immunohistochemical analysis was performed on these and 20 negative lymphoma staging BM specimens. Of 127 BM specimens, 74 were positive and 53 were negative for residual PCM by conventional criteria. Of 74 BM specimens positive by conventional criteria, 59 (80%) demonstrated CD56 (strong+) PCs in clusters and/or with cytologic atypia. Of the 53 BM specimens negative by conventional criteria, 3 showed CD56 (strong+) morphologically atypical PCs in clusters or scattered. CD56 immunohistochemical analysis is useful for detecting residual PCM, particularly in morphologically equivocal cases in which light chain restriction cannot be demonstrated, and may serve as a potential response criterion.