Macrophages differentiate into osteoclasts upon stimulation by RANKL. In inflammatory lesions such as rheumatoid arthritis, direct stimulation of macrophages by inflammatory cytokines promotes osteoclast differentiation, which is speculated to contribute to pathological bone destruction. Therefore, inhibition of inflammatory osteoclast differentiation may ameliorate bone destruction. All-trans retinoic acid (ATRA), the active form of vitamin A, activates retinoic acid receptor (RAR), resulting in potent inhibition of RANKL-induced osteoclast differentiation. ATRA also activates retinoid X receptor (RXR). The importance of RXR in inhibiting osteoclast differentiation is unknown. Bexarotene, a synthetic retinoid that exhibits anti-tumor activity, is an agonist specific for RXR. To clarify the effect of RXR-stimulation on osteoclast differentiation, we compared the effects of ATRA and bexarotene on differentiation of RANKL-induced or inflammatory (TNF/IL-6-induced) osteoclasts. Bexarotene inhibited their differentiation by suppressing the expression of Nfatc1, a master regulator of osteoclast differentiation as well as ATRA, suggesting the importance of RXR in suppressing osteoclast differentiation. Bexarotene may contribute to the treatment of pathological bone destruction in inflammatory lesions as drug repositioning candidates.