In multiple myeloma, malignant plasma cells from most patients with active disease proliferate spontaneously when cultured for 5 days in vitro. This spontaneous proliferation is related to the endogenous production of interleukin-6 (IL-6), the major myeloma-cell growth factor. A 50% inhibitory dose (100 U/mL) of human recombinant gamma- interferon (hr gamma-IFN) blocked the proliferation of myeloma cells almost completely in all 19 patients analyzed. This inhibition was not caused by suppression of endogenous IL-6 production and was also observed in the presence of an excess of hrIL-6. hr gamma-IFN was also completely inhibitory in four human myeloma cell lines (HMCL) whose growth is totally dependent on the addition of exogenous hrIL-6. This inhibition was associated with a 47% to 73% decrease in membrane IL-6- binding gp80 protein as well as with a 90% decrease in the amount of gp80 mRNA in HMCL. These results are in line with recent reports indicating that gamma-IFN inhibited several IL-6-dependent biologic processes. They suggest a need to reconsider why previous preliminary clinical trials failed to demonstrate a beneficial effect of gamma-IFN in multiple myeloma.