Interferon-α (IFN-α) is currently used for the therapy of multiple myeloma (MM) though it is only effective in some patients. IFN-α induces apoptosis in some MM cell lines and it has been proposed to occur through an autocrine loop involving Apo2L/TRAIL. We have analysed the sensitivity to IFN-α and Apo2L/TRAIL of five MM cell lines and found no correlation between the apoptosis inducing ability of both cytokines. IFN-α-induced apoptosis in MM cells was not prevented by a caspase-8 selective inhibitor (Z-IETD-fmk) or blocking Apo2L/TRAIL. However, human monocytes treated with IFN-α release bioactive Apo2L/TRAIL to culture media which was cytotoxic for MM cells resistant to IFN-α. We propose that Apo2L/TRAIL released from IFN-α-stimulated blood monocytes would be a major mediator of the anti-myeloma effect of IFN-α in vivo.