DEL-1 (developmental endothelial locus–1) is an endothelial cell–secreted protein that regulates LFA-1 (lymphocyte function–associated antigen–1) integrin–dependent leukocyte recruitment and inflammation in various tissues. We identified a novel regulatory mechanism of DEL-1 in osteoclast biology. Specifically, we showed that DEL-1 is expressed by human and mouse osteoclasts and regulates their differentiation and resorptive function. Mechanistically, DEL-1 inhibited the expression of NFATc1, a master regulator of osteoclastogenesis, in a Mac-1 integrin–dependent manner. In vivo mechanistic analysis has dissociated the anti-inflammatory from the anti–bone-resorptive action of DEL-1 and identified structural components thereof mediating these distinct functions. Locally administered human DEL-1 blocked inflammatory periodontal bone loss in nonhuman primates—a relevant model of human periodontitis. The ability of DEL-1 to regulate both upstream (inflammatory cell recruitment) and downstream (osteoclastogenesis) events that lead to inflammatory bone loss paves the way to a new class of endogenous therapeutics for treating periodontitis and perhaps other inflammatory disorders.