Interleukin‐6 (IL‐6) is the major growth factor for human myeloma cells, exerting its effect through the IL‐6 receptor (IL‐6R). A soluble form of IL‐6R (sIL‐6R) has been identified, which increases the sensitivity of myeloma cells to IL‐6. In patients with multiple myeloma (MM), serum concentrations of sIL‐6R are elevated and associated with poor prognosis. The present study was undertaken to determine whether proteolytic cleavage of IL‐6R could contribute to sIL‐6R release from human myeloma cells, and also to identify the class of proteinase responsible for this event. Human myeloma cell lines were shown to express IL‐6R upon their surface and also to release sIL‐6R into culture supernatants. In addition, phorbol 12‐myristate 13‐acetate (PMA) stimulated a loss of IL‐6R from the cell surface, with a corresponding increase in the concentration of sIL‐6R in the supernatant. Inhibitors of serine and cysteine proteinases, and tissue inhibitor of metalloproteinase (TIMP) ‐1 and TIMP‐2, were shown to have no effect on the magnitude of sIL‐6R release. In contrast, TIMP‐3 and a hydroxamate‐based metalloproteinase inhibitor (BB‐94), inhibited both constitutive and PMA‐induced release of sIL‐6R. Myeloma cells freshly isolated from the bone marrow of a patient with MM were also shown to express IL‐6R upon their surface, and to shed this receptor in response to PMA. These data demonstrate that increased proteolytic cleavage of IL‐6R, mediated by a non‐matrix‐type metalloproteinase, is likely to contribute to the elevated concentrations of sIL‐6R found in the serum of patients with MM. Inhibition of sIL‐6R release by hydroxamate‐based metalloproteinase inhibitors may represent a novel therapeutic approach to the treatment of MM.