The lifespan of patients with HIV infection has been significantly increased due to the last few decades of therapeutic improvement, simultaneously age-related comorbidities including bone diseases, have been needed to prevent or reduce bone loss in patients with HIV. Since C-C chemokine receptor 5 (CCR5) was discovered to be a critical co-receptor for macrophage-tropic HIV, the inhibitors against CCR5 such as Maraviroc have been used for the HIV patients. Epidemiological and pathological findings in human studies reported that functional loss in CCR5 correlate with the resistance to bone destruction diseases as well as HIV transmission. This possible association between loss of CCR5 and resistance to bone loss has been largely interpreted by the changes in the inflammatory and immunomodulatory responses caused by functional loss of CCR5, thus affecting the readout of bone metabolism. However, pathophysiological roles of CCR5 in bone metabolism have not been experimentally well documented. This study demonstrated that the blockade of CCR5 using its specific antibodies impaired in vitro human osteoclastogenesis with disorganized actin rings, but not osteoblastogenesis. Ccr5-deficient (Ccr5-/-) mice with dysfunctional osteoclasts were resistant to osteoporotic stimulation via the administration of receptor activator of nuclear factor kappa-B ligand (RANKL), which induces osteoporosis independently of the inflammatory and immunomodulatory responses. Furthermore, the CCR5-mediated pathway in osteoclasts transcriptionally and post-translationally enhanced the integrin-mediated and chemokine pathways. The present study experimentally provides further evidence that CCR5 plays an essential role in bone destructive diseases through the functional regulation of osteoclasts, thus suggesting the skeletal benefit of CCR5-targetting therapy.