Signal transduction and activator of transcription (Stat) 3 is a transcription factor that is activated by a variety of cytokines and growth factors, including IL-6 family cytokines. These cytokines regulate bone homeostasis and have been reported to regulate the differentiation of osteoblasts and osteoclasts through Stat3 activation in vitro, but the in vivo physiological role of Stat3 in bone homeostasis is unknown. Here, we report that gp130 knock-in mice gp130(F759/F759), in which IL-6 family cytokine-mediated Stat3 activation is enhanced, showed an osteosclerotic phenotype. To further clarify the role of Stat3 in bone formation, we generated mice with osteoblast-specific disruption of the Stat3 gene via the Cre-LoxP recombination system using alpha1(I)-collagen promoter Cre transgenic mice. The alpha1(I)Cre;Stat3(flox/-) mice showed an osteoporotic phenotype because of a reduced bone formation rate. Thus, the Stat3 signal in osteoblasts plays a pivotal role in bone formation in vivo.