BACKGROUND: Despite IFNalpha has been used extensively in the treatment of multiple myeloma (MM), there are also several reports suggesting that IFNalpha may aggravate isease in some MM patients. That means the effect of IFNalpha on the growth of myeloma cells in vivo may be different. In this study, we selected two human myeloma cell lines that vary remarkably in response to IFNalpha and focused on elucidating the mechanism of differential IFNalpha responsiveness. RESULTS: Sko-007 is a myeloma cell line whose growth is arrested by IFNalpha; however, IFNalpha promoted the proliferation of the other myeloma cell line U266. We observed that the growth-stimulation effect of IFNalpha on U266 cells did not result from up-regulation of the IL-6 receptors on cell surface; while IFNalpha treatment on Sko-007 cells significantly reduced gp130 expression. Moreover, the transcription factors STAT3 and STAT1, which are involved in the JAK/STAT signal transduction pathway, can be activated in both IFNalpha-stimulated and -inhibited myeloma cell lines; while the activation of the protein kinase ERK, which is involved in the Ras/MAPK signal transduction pathway, can be down-regulated in IFNalpha-arrested Sko-007 cells and up-regulated in IFNalpha-stimulated U266 cells. In addition, both IFNalpha-induced growth-stimulation effect and the up-regulated activation of ERK in U266 cells were efficiently inhibited by PD98059, the specific inhibitor of MAPK/ERK kinase (MEK). CONCLUSION: Myeloma cells responsiveness to IFNalpha is heterogeneous and the activation state of ERK in the Ras/MAPK signalling pathway mainly contributed to this difference.