The relationship between oxidative stress and bone mineral density or osteoporosis has recently been reported. As bone loss occurring in osteoporosis and inflammatory diseases is primarily due to increases in osteoclast number, reactive oxygen species (ROS) may be relevant to osteoclast differentiation, which requires receptor activator of nuclear factor-κB ligand (RANKL). Tumor necrosis factor-α (TNF-α) frequently present in inflammatory conditions has a profound synergy with RANKL in osteoclastogenesis. In this study, we investigated the effects of α-lipoic acid (α-LA), a strong antioxidant clinically used for some time, on osteoclast differentiation and bone resorption. At concentrations showing no growth inhibition, α-LA potently suppressed osteoclastogenesis from bone marrow-derived precursor cells driven either by a high-dose RANKL alone or by a low-dose RANKL plus TNF-α (RANKL/TNF-α). α-LA abolished ROS elevation by RANKL or RANKL/TNF-α and inhibited NF-κB activation in osteoclast precursor cells. Specifically, α-LA reduced DNA binding of NF-κB but did not inhibit IKK activation. Furthermore, α-LA greatly suppressed in vivo bone loss induced by RANKL or TNF-α in a calvarial remodeling model. Therefore, our data provide evidence that ROS plays an important role in osteoclast differentiation through NF-κB regulation and the antioxidant α-lipoic acid has a therapeutic potential for bone erosive diseases.