Previous studies showed that 2-methoxyestradiol (2ME2) could suppress the proliferation of myeloma cells and induce their apoptosis. In the present study, we found that treatments with low-concentration of 2ME2 resulted in some maturing morphological changes of myeloma cells. Flow cytometric analysis showed that the expression of CD49e on the myeloma cells surface was significantly increased by 2ME2. Moreover, 2ME2 increased the secretion of light chain protein remarkably. Furthermore, the expressions of transcription factor XBP-1 mRNA and protein were also up-regulated. These results demonstrated that 2ME2 at low-concentration could induce differentiation of the myeloma cells, which would provide a new, safe strategy for myeloma therapy.