While it has been established that IFN-γ is a strong activator of macrophages and a potent inhibitor of osteoclastogenesis in vitro, it is also known that this cytokine is produced in particular settings of inflammatory bone loss, such as infection and psoriatic arthritis. Because of the different kinetics between rapid IFN-γ macrophage activation (<24 hours) and the slower receptor-activator of NFκB ligand (RANKL) osteoclast differentiation (7 days), we postulated that IFN-γ would have different effects on early-stage and late-stage osteoclast precursors. In RAW264.7 cells and primary splenocyte cultures, pretreatment with RANKL rendered these cells resistant to maximally anti-osteoclastogenic doses of IFN-γ. These cells were also resistant to IFN-γ-induced nitric oxide production, morphological change, and surface upregulation of CD11b and receptor-activator of NFκB, suggesting that early exposure of osteoclast precursors to RANKL induces a broad resistance to the cellular effects of IFN-γ. Changes in STAT1 activation did not correlate with this resistance, as IFN-γ activated STAT1 equally in both early-stage and late-stage pre-osteoclasts. Furthermore, we failed to observe changes in TRAF6 expression following IFN-γ treatment in pre-osteoclasts. Together these data support a model of inflammatory bone loss in which early exposure to RANKL can prime osteoclast precursors to form in the presence of high levels of IFN-γ using mechanisms independent of the signal molecules STAT1 and TRAF6.