Accurate quantification of plasma cells in bone marrow samples is essential for the diagnosis, classification and prognosis of plasma-cell dyscrasias. Published comparisons between aspirate/trephine morphology, flow cytometry and immunohistochemistry are lacking. Bone marrow plasma cells from 100 patients with plasma cell myeloma or monoclonal gammopathy of undetermined significance were quantified by a 500-cell differential count on Romanowsky-stained aspirate slides, flow-cytometry gating of CD38bright+/CD138+ cells, hematoxylin and eosin trephine section examination and CD138 trephine immunohistology. The results of quantification by the different methods were compared. Compared to other methods, CD138 trephine immunohistology consistently demonstrated greater plasma-cell infiltration. Immunohistology is the most sensitive method for assessment of plasma-cell infiltration at diagnosis or post-therapy, especially in patients with minimal bone marrow involvement.