Objectives: The objectives of this study are to determine the effects of thapsigargin-induced ER stress on the IL 1βstimulated and RANKL-mediated osteoclast formation and its mechanisms. Materials and Methods: Bone marrow cells (BMCs) from 5-week-old male imprinting control region (ICR) mice were cultured with M-CSF and RANKL in the presence or absence of IL-1β and thapsigargin. The formation of osteosclasts was evaluated with tartrate-resistant acid phosphatase (TRAP) staining and resorption pit assay with dentine slice. The expression of c-FOS, NFATc1 and intracellular MAPK signalings, including p-ERK, p-p38, p-JNK and NF-kB were examined by immunoblotting or semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). Results: Thapsigargin-induced ER stress increased the IL-1β -stimulated and RANKL-mediated formation of osteoclasts by upregulation of c-FOS, NFATc1, MAPKs and NF-kB. Conclusions: These results suggest that ER stress is involved in IL-1β-stimulated and RANKL-mediated osteoclast differentiation, and indicate that the modulation of ER stress-associated mechanisms might be a useful therapeutic target for managing osteoporosis or bone destruction in inflammatory diseases including rheumatoid arthritis.