The effects of interleukin-3 (IL·3) and interleukin-6 (IL·6) on nonadherent mononuclear cells (NMC) from the peripheral blood of 28 patients with multiple myeloma (MM), 3 patients with monoclonal gammopathy of undetermined significance (MGUS), and 3 normal controls were investigated. In 15 of 27 evaluable patients with MM, monoclonal-cytoplasmic-immunoglobulin (clg)-positive plasma cells appeared from the T-cell-depleted NMC after 10 days of culture in the presence of IL·3 and IL·6. These changes were not observed in the T cell fraction of myeloma blood or in the T-cell-depleted NMC obtained from cases of MGUS or from normal controls. The percentage of clg-positive plasmacytoid cells after 10 days of culture was significantly higher in the presence of both IL·3 and IL·6 than with each interleukin alone or the control medium. Furthermore, these changes were often observed in untreated patients. These findings suggest that myeloma precursor cells exist in the peripheral blood of MM patients, especially at diagnosis, and differentiate into clg-positive cells in the presence of IL·3 and IL·6. This assay may be useful in discriminating the early stage of myeloma from MGUS.