AbstractOsteoclasts are the primary cells responsible for bone resorption. Osteoclast formation and bone resorption activities involve processes tightly controlled by a network of cytokines. The presence of interferon gamma (IFN‐γ) receptors on osteoclasts is a necessary prerequisite for IFN‐γ to directly affect osteoclastic activity. To date, the presence of the IFN‐γ receptor on osteoclasts has not been established. This study provides evidence that osteoclasts express the IFN‐γ receptor. Specific binding of IFN‐γ to the osteoclastic receptor stimulates osteoclastic superoxide generation. The p91 and p47 components of the NADPH oxidase increase after IFN‐γ stimulation and may account for the enhanced superoxide generation. Antisense experiments targeting p91 and p47 subunits abrogate the increased osteoclastic superoxide production stimulated by IFN‐γ. Thus, superoxide generation by osteoclasts is stimulated by activation of a functional IFN‐γ receptor on the osteoclast. J. Cell. Biochem. 84: 645–654, 2002. © 2001 Wiley‐Liss, Inc.