Plasma cell myeloma (PCM) exhibits immunophenotypic aberrancies that can be used for minimal residual disease (MRD) detection after therapy. The authors sought to determine whether non-neoplastic plasma cells, especially in the bone marrow (BM) post various therapies, would exhibit immunophenotypic variations interfering PCM MRD detection. The authors studied the flow cytometric immunophenotypes of non-neoplastic plasma cells from 50 BM specimens, including 12 untreated BM and 38 BM specimens from patients with non-plasmacytic haematological malignancies undergoing various therapies, and compared with 59 BM specimens positive for PCM MRD. Non-neoplastic plasma cells showed heterogeneous expressions of CD45 (78% (41–100)) and CD19 (80% (52–97)), and were negative for CD20 and CD117. CD56 was observed in a small subset (6% (0–37)) and CD28 in a larger subset (15% (0–59)) of non-neoplastic plasma cells, with the latter more frequently expressed in post-treatment BMs (p=0.01). However, despite a partial immunophenotypic overlap, PCM cells could be reliably discriminated from non-neoplastic plasma cells by the presence of a higher number of aberrancies (3 (1–6) vs 0 (0–2)) and stronger intensity and uniformity of aberrant expression (p<0.001 in each marker using a cut-off value). In addition, simultaneous assessment of cytoplasmic κ/λ with surface markers detected light chain restriction in all 59 PCM cases. In conclusion, non-neoplastic plasma cells in BM are more immunophenotypically heterogeneous than previously understood; however, these immunophenotypic variations differ from those of PCM. With advances in multicolour flow cytometry and application of recently validated markers, PCM MRD may still be reliably distinguished from non-neoplastic plasma cells.