Estrogen inhibits osteoclastogenesis and induces osteoclastic apoptosis; however, the molecular mechanisms remain controversial. Recently, a group has demonstrated that osteoclasts are a direct target for estrogen because estrogen stimulates transcription of the Fas Ligand (FasL) gene in osteoclasts, which in turn causes cell death through an autocrine mechanism. In contrast, other groups have shown that the cells are an indirect target for estrogen because estrogen fails to stimulate the transcription of that in osteoclasts. Thus, two quite different molecular mechanisms have been suggested to explain the effects of estrogen in osteoclastic apoptosis. Here we show that the proapoptotic effect of estrogen during osteoclastogenesis is regulated by a posttranscriptional increase in FasL production by down-regulated microRNA-21 (miR-21) biogenesis. Previously, we reported that miR-21 is highly expressed in osteoclastogenesis. We found that estrogen down-regulates miR-21 biogenesis so that FasL, the targets of miR-21, protein levels are posttranscriptionally increased that induce osteoclastic apoptosis. Moreover, the gain-of-function of miR-21 rescued the apoptosis. In addition, we failed to detect estrogen-enhanced FasL levels at mRNA levels. Thus, osteoclastic survival is controlled by autocrine actions of FasL regulated by estrogen and miR-21 plays a central role during estrogen-controlled osteoclastogenesis. J. Cell. Biochem. 114: 1217-1222, 2013. © 2012 Wiley Periodicals, Inc.