The effect of indomethacin on bone resorption was studied in an organ culture system, using calvarial bones from 6–7-day-old mice. It was found that indomethacin inhibited spontaneous bone resorption, as estimated by decreased release of45Ca, Ca2+and P,. Indomethacin reduced the release ofβ-glucuronidase,β-galactosidase andβ-N-acetylglucosaminidase, diminished glucose consumption and lactate production, but showed no effect on the release of lactate dehydrogenase. No inhibitory effect of indomethacin on the release of45Ca stimulated by parathyroid hormone, prostaglandin E2or 1α(OH)D3could be registered. 5,8,11,14-eicosatetraynoic acid, an inhibitor of both cyclo- and lipoxygenase pathway of arachidonate metabolism, reduced the spontaneous release of45Ca, whereas the selective lipoxygenase inhibitor 5,8,11-eicosatriynoic acid was without effect. The results presented indicate that indomethacin may have an inhibitory effect upon the osteoclasts, probably by decreased metabolism of arachidonic acid via the cyclo-oxygenase pathway. A possible relationship between this rinding and the pathogenesis of rapid destruction of articular bone in osteoarthritic patients treated with indomethacin is discussed.