The Pim1 (Proviral Integration site for Moloney leukemia virus 1) protein is a serine/threonine kinase that is essential for cell proliferation, apoptosis, and innate-immune responses. Our study shows for the first time that Pim1 promotes osteoclast resorptive function without affecting osteoclast numbers. Specifically, we found that mice lacking Pim1 (Pim1-/-) developed increased trabecular bone mass and indices such as trabecular bone-mass density. This was due to the direct phosphorylation of TRAF6 by Pim1 in mature osteoclasts, which activated the Akt-GSK3β signaling pathway. This in turn promoted the acetylation and consequent stabilization of microtubules, which permitted the formation of the osteoclast sealing zone. In vivo experiments then showed that when mice with lipopolysaccharide-induced bone loss or tumor-induced osteolysis were treated with SGI-1776, a Pim inhibitor that is more selective for Pim1, the bone loss was significantly ameliorated. Thus, Pim1 plays an important role in osteoclast function and may be a novel therapeutic target for bone-related diseases