In humans, type I interferon (IFN) is a family of 17 cytokines, among which the α subtypes and the β subtype are differentially expressed. It has been suggested that IFN-β activates a specific signaling cascade in addition to those activated by all type I IFNs. Nevertheless, no true biological relevance for a differential activity of α and β IFN subtypes has been identified so far. Because type I IFNs are critical for the regulation of osteoclastogenesis in mice, we have compared the effect of IFN-α2 and IFN-β on the differentiation of human monocytes into osteoclasts. Primary monocytes undergoing osteoclastic differentiation are highly and equally sensitive to both α2 and β IFNs as determined by measuring the induction levels of several IFN-stimulated genes. However, IFN-β was 100-fold more potent than the α2 subtype at inhibiting osteoclastogenesis. Expression profiling of the genes differentially regulated by IFN-α2 and IFN-β in this cellular system revealed the chemokine CXCL11 as the only IFN-induced gene differentially up-regulated by IFN-β. We show that recombinant CXCL11 by itself inhibits osteoclastic differentiation. These results indicate that autocrine-acting CXCL11 mediates, at least in part, the regulations of osteoclastogenesis by type I IFNs.