IL-23 activates the synthesis and production of leukotriene B 4 (LTB 4) in myeloid cells, which modulate inflammatory arthritis. In this study we investigated the role of LTB 4 and its receptor LTB 4 R1 (BLT1) in synovial inflammation and osteoclast differentiation. Specifically, we used IL-23 in vivo gene transfer to induce arthritis in mice and showed that elevated serum LTB 4 and synovial expression of 5-lipoxygenase correlated with increased disease severity by histological evaluation and paw swelling compared with GFP gene transfer controls. To further investigate the effect of the LTB 4 pathway in bone loss, we performed osteoclast differentiation assays by stimulating with M-CSF and receptor activator of NF-κB ligand bone marrow cells derived from BLT1+/+ and/or BLT1−/− mice and used quantitative PCR for gene expression analysis in terminally differentiated osteoclasts. Deficiency in BLT1 resulted in the upregulation of osteoclast-related genes and an increase in the formation of giant, multinucleated TRAP+ cells capable of F-actin ring formation. Additionally, BLT1 deficiency showed an increase of phosphorylated NF-κB and phosphorylated IκB levels in osteoclasts. We also performed real-time calcium imaging to study the effect of BLT1 deficiency in receptor activator of NF-κ-B ligand–induced activation of intracellular calcium flux in vitro. Our data show that LTB 4 and its receptor BLT1 exacerbate synovial inflammation in vivo and bone resorption in vitro, suggesting that LTB 4 and BLT1 could be effectively targeted for the treatment of musculoskeletal diseases.