Irijimasides A-E (1-5), a series of new 14-membered macrolide glycosides, were isolated from a marine cyanobacterium collected in Okinawa. The gross structures of 1-5 were established by spectroscopic analysis, including 2D NMR, while absolute stereostructures were determined based on NOESY spectra, chemical derivatization, and ECD data. All five macrolides suppressed receptor activator of nuclear factor-κB ligand (RANKL)-induced tartrate-resistant acid phosphatase (TRAP) activity in mouse RAW264 macrophage cells, indicating that these compounds inhibit osteoclast formation.