AbstractPlasma cell enumeration and immunophenotyping has been shown to be of value in predicting the outcome for patients with myeloma. Detection of abnormal plasma cells at a leukocyte level >0.01% at the end of therapy predicts early relapse. Although clonally related populations at varying stages of differentiation are reported to be present in myeloma, only the CD138+ fraction has been shown to directly correlate with the outcome. In addition, the plasma cell immunophenotype in monoclonal gammopathy of undetermined significance (MGUS) is reported to correlate with the risk of progression to myeloma. This protocol provides a four‐color flow cytometry method for enumeration and classification of plasma cells in both diagnostic and post‐treatment samples. Plasma cells are identified by strong expression of CD38 and CD138. Neoplastic plasma cells are separated from their normal counterparts by aberrant expression of CD19 and other relevant markers in combination with intracellular immunoglobulin light chain restriction.