Multiple myeloma (MM) plasma cells are apoptosis resistant. The system of Fas with its ligand (Fas-L) participates actively in the extrinsic apoptotic system. In oncology, its role is controversial, since it has been reported both to suppress and promote tumor growth. The aim of this study was to measure serum levels of soluble Fas-L (sFas-L) in patients with active MM and to correlate them with markers of disease activity. We studied 57 patients with active MM, along with 22 healthy controls. We measured serum levels of sFas-L and interleukin-6 (IL-6) by enzyme-linked immunosorbent assays, as well of beta-2 microglobulin (B2M), C-reactive protein (CRP) and lactate dehydrogenase (LDH). We also measured the degree of bone marrow infiltration. All parameters were increased in patients, compared with controls (p < 0.001 for all cases) and also in parallel with disease stage (p < 0.001 for all cases). Positive correlations were noted between serum levels of sFas-L with IL-6, infiltration (p < 0.001 for both cases) and LDH (p < 0.04), but not with CRP and B2M. We suggest that the system of Fas/Fas-L participates actively in MM progression in a complex manner and that serum levels of sFas-L may reflect disease progression. Further studies are needed to determine its usefulness as a marker of disease activity.