Because of the increasing use of IFN-αin both induction and maintenance therapy for multiple myeloma (MM), its effect on growth and apoptosis of myeloma cells is important to consider. To investigate the role of IFN-αon the growth of myeloma cells, we have studied its effects on the response of interleukin 6 (IL-6)-dependent myeloma cell line (ANBL6) and IL-6-independent myeloma cell line (C2E3) in the presence of IL-6 and dexamethasone (Dex). We found that although IFN-αis a potent inhibitor of proliferation, it has only a minimal effect on induction of apoptosis. Moreover, we found IFN-α as well as IL-6 can significantly suppress dexamethasone-induced apoptosis. The suppression of apoptosis is concurrent with the induction of both AP-1 and STAT binding activity. We also found that IL-6 but not IFN-αup-regulates Bcl-X L expression. However, IL-6-mediated Bcl-X L expression is suppressed in the presence of Dex. Therefore, the expression of Bcl-X L does not account for the protection of Dex-induced apoptosis by IFN-αand IL-6. Taken together, our results suggest that IFN-αmay counteract the beneficial effects of corticosteroids or perhaps other apoptosis inducing agents in the treatment of myeloma.