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We investigated the presence of OPG and bone\u2010resorbing cytokines, the potential of osteoclastic differentiation in joint fluid from failed total hip arthroplasty (THA), and the inhibitory effect of OPG on osteoclast formation <jats:italic>in vitro<\/jats:italic> induced by the joint fluid. The study was aimed to clarify one important step in the cascade of periprosthetic osteolysis in the process of implant loosening. OPG levels in failed THA joint fluid of 20 cases were significantly lower than osteoarthritis (OA) joint fluid of 15 cases (<jats:italic>p<\/jats:italic> &lt; 0.001). The levels of bone\u2010resorbing cytokines, interleukin (IL)\u20101\u03b2, and IL\u20106 were significantly higher in failed THA joint fluid than OA fluid (<jats:italic>p<\/jats:italic> &lt; 0.001 and <jats:italic>p<\/jats:italic> = 0.001, respectively). Marked osteoclast formation was observed in the presence of failed THA joint fluid in the mouse coculture system, when compared to OA fluid (<jats:italic>p<\/jats:italic> &lt; 0.001). The addition of 100 ng\/mL OPG to the mouse coculture system completely inhibited osteoclast formation in the presence of failed THA joint fluid (<jats:italic>p<\/jats:italic> &lt; 0.001). The data suggest that low levels of OPG combined with higher IL\u20101\u03b2 and IL\u20106 levels represent the potential of osteoclast differentiation and its activation in failed THA joint fluid. Inhibition of osteoclastogenesis <jats:italic>in vitro<\/jats:italic> by OPG suggests that a low level of OPG with elevated bone resorbing cytokines contributes to periprosthetic osteolysis via osteolytic joint fluid, thus leading to THA prosthesis loosening.\u00a9 2001 John Wiley &amp; Sons, Inc. 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