Presence of normal plasma cells (PCs), hemodilution of bone marrow aspirate, and changes in the immunophenotype are important considerations in minimal residual disease (MRD) assessment in multiple myeloma (MM). We evaluated 124 subjects-107 with MM, 11 with Hodgkin lymphoma, and 6 allogeneic stem cell transplantation donors-for the immunophenotype of neoplastic, reactive, and normal PCs respectively. Of the patients with MM, 36 were evaluated for MRD and 23 for a change in immunophenotype after chemotherapy. The immunophenotype of normal and reactive PCs was similar and differed from that of neoplastic PCs with respect to CD19, CD45, CD56, CD52, CD20, and CD117. At least 2 antigens were aberrantly expressed in all cases and 3 in 90.7% of MM cases. A change in the immunoprofile of PCs was observed in 18 (78%) of 23 cases. By using flow cytometry, we detected MRD in all samples, and a neoplastic PC index (percentage of neoplastic PCs/total bone marrow PCs) of less than 30 could differentiate immunofixation (IFx)- from IFx+ samples (complete and partial responders, respectively).