Cell/matrix detachment is a general inducer of programmed cell death, an event mediated by loss of integrin/ligand association. Because α_vβ₃ is the major integrin expressed by the osteoclast, we asked whether its occupancy promotes survival of the resorptive cell. Thus, we generated wild-type preosteoclasts and placed them on selective matrix proteins. Consistent with the posture that α_vβ₃ occupancy promotes survival, preosteoclasts plated on native collagen, a matrix not recognized by the integrin, undergo apoptosis 4-fold faster than those on the α_vβ₃ ligand, vitronectin. To further explore the role of α_vβ₃ in osteoclast apoptosis, wild-type and β₃^−/− preosteoclasts were suspended and apoptosis determined, with time. β₃^−/− preosteoclasts, in suspension, undergo a rate of apoptosis only 40–60% of that of their wild-type counterparts, indicating that unoccupied α_vβ₃ transmits a positive death signal that we find regulated by caspase-8. Attesting to specificity of the unoccupied integrin-transmitted death signal, apoptosis in the absence of α_vβ₃ is mediated by capsase-9. We have shown that the resorptive defect of β₃^−/− osteoclasts is rescued by wild-type β₃ cDNA but not by one bearing a S⁷⁵²P mutation. To determine whether the same holds true regarding osteoclast apoptosis, we constructed lentivirus vectors encoding green fluorescent protein, wild-type β₃, or β₃^S752P. Once again, native β₃^−/− preosteoclasts were protected against apoptosis. Similar to its effect on bone resorption, transduced wild-type β₃ normalizes the apoptotic rate of β₃^−/− preosteoclasts. Unexpectedly, however, β₃^S752P transductants also die at a rate indistinguishable from wild type. Thus, unoccupied α_vβ₃ integrin regulates osteoclast apoptosis via a component of the integrin that is different than that regulating resorption.