TNFalpha is pivotal to the pathogenesis of inflammatory and possibly postmenopausal osteolysis. Much recent work has clarified mechanisms by which TNFalpha promotes osteoclastogenesis, but the means by which it activates osteoclasts to resorb bone remain uncertain. We found that very low concentrations of TNFalpha promoted actin ring formation, which correlates with functional activation in osteoclasts, both in osteoclasts formed in vitro and extracted from newborn rats. TNFalpha was equipotent with RANKL for this action. Activation by TNFalpha was unaffected by blockade of RANKL by OPG, its soluble decoy receptor, suggesting that this was due to a direct action on osteoclasts. Bone resorption was similarly directly and potently stimulated, in a RANKL-independent manner in osteoclasts, whether these were formed in vitro or in vivo. Interestingly, TNFalpha promoted actin ring formation at concentrations an order of magnitude below those required for osteoclastic differentiation. Moreover, TNFalpha strongly synergized with RANKL, such that miniscule concentrations of TNFalpha were sufficient to substantially augment osteoclast activation. The extreme sensitivity of osteoclasts to activation by TNFalpha suggests that the most sensitive osteolytic response of bone to TNFalpha is through activation of existing osteoclasts; and the strong synergy with RANKL provides a mechanism whereby increased osteolysis can be achieved without disturbance to the underlying pattern of osteoclastic localization.