The search for bone marrow clone neoplastic precursors in the peripheral blood of multiple myeloma (MM) patients has been the subject of a number of studies which, using different methodological approaches, have led to conflicting results. With the aim of contributing toward resolving this controversy, immunoglobulin (Ig) gene rearrangement in the bone marrow mononuclear cells (BMMC) and B-lymphocyte enriched peripheral cells (BePBC) of 11 appropriately selected advanced MM patients was studied by means of Southern blotting. Peripheral mononuclear cells (PBMC) and BePBC were studied immunophenotypically by evaluating the presence of cytoplasmic Ig positive cells (CyIg+) and CD19/PCA-1 reactivity. A pattern of Ig gene rearrangement identical to that observed in the respective BMMC was found in only two patients who, moreover, had a significant number of CyIg+ cells. Ig gene rearrangement was not found in any of the remaining patients who showed no evidence of the presence of CyIg+ cells, although there were CD19/PCA-1 positive cells. Consequently, the significance of the presence of malignant pre-plasma cell peripheral B-lymphocytes needs to be reconsidered and, in any case, these cells should be looked for in cell populations greatly enriched in B-lymphocytes and, above all, completely lacking in plasma cells or CyIg+ cells.