OBJECTIVE: To investigate the effects of lenalidomide on lipopolysaccharide (LPS)-induced osteoclastogenesis and bone resorption. STUDY DESIGN: The cytotoxicity of lenalidomide on bone marrow stromal cells (BMSCs) was evaluated by CCK-8. The effect of lenalidomide on bone resorption induced by lipopolysaccharide was detected in vivo. RESULTS: The IC50 of lenalidomide in BMSCs was 16.5 nM. Lenalidomide improved the repair of LPS-induced cranial bone resorption. The qPCR result and histological result shows that lenalidomide attenuated osteoclast formation and downregulated the osteolytic level in a dose-dependent manner, and osteoblastogenesis was upregulated with dosage association. CONCLUSION: Lenalidomide could potently inhibit bone resorption and osteoclastogenesis while promoting osteoblastogenesis. Our findings indicate the potential use of lenalidomide for treatment of osteolytic lesions. © Science Printers and Publishers, Inc.