Interleukin 6 (IL-6) influences the growth and survival of multiple myeloma (MM) cells via the activation of multiple signalling cascades. Although sphingosine kinase (SPHK) signalling is known to play important roles in the regulation of cell proliferation and apoptosis, the role of SPHK activation in IL-6 signalling and in the pathology of MM remains unclear. This study found that IL-6 activated SPHK in MM cells, which mediates the suppressive effects of IL-6 on MM cell apoptosis. Both MM cell lines and primary MM cells constitutively expressed SPHK, and treatment of MM cells with IL-6 resulted in activation of SPHK in a concentration-dependent manner. Specific inhibitors of the phosphatidylinositol-3 kinase and extracellular signal-regulated kinase/mitogen-activated protein kinase pathways blocked the IL-6-induced activation of SPHK. It was further demonstrated that IL-6-induced activation of SPHK inhibited dexamethasone-induced apoptosis of MM cells. IL-6 stimulation or retroviral-mediated overexpression of SPHK1 in MM cells resulted in increased intracellular SPHK activity and upregulation of myeloid cell leukaemia-1 (Mcl-1), leading to increased cell proliferation and survival. Conversely, inhibition of SPHK1 by small interfering RNA reduced IL-6-induced upregulation of Mcl-1 and blocked the suppressive effect of IL-6 on MM cell apoptosis. Taken together, these results delineate a key role for SPHK activation in IL-6-induced proliferation and survival of MM cells, and suggest that SPHK may be a potential new therapeutic target in MM.