This report shows that ectopic bone formation, a serious problem in orthopedic surgery, can be controlled in an animal model by local application of EHDP (disodium-ethane-1-hydroxy-1,1-diphosphonate). The results might be particularly pertinent to the clinical problem of preventing the recurrence of ectopic bone after surgical excision. Male New Zealand white rabbits were treated with immobilization and intermittent passive manipulation of the right knee. The treatment caused bone formation in the quadriceps muscle, which was visible on radiographs after 3 weeks. In this model, the effect of methacrylate implants containing EHDP was studied. A concentration of 16 g EHDP/100 g methacrylate inhibited bone formation in experimental cortical defects. Release of radiolabeled EHDP was studied in an in vitro system. The release of the drug was approximately 20 mg/day and implant initially, decreasing to about 0.1 mg/day/implant after 30 days. Standardized implants containing 16 g EHDP/100 g were then surgically attached to the femur, and the ectopic bone formation created by immobilization and intermittent manipulation was compared with that in rabbits treated with implants but without EHDP. The ectopic bone was measured from lateral and frontal radiograms and from radiograms of serial transverse sections of the thigh. We found that the EHDP implants were capable of preventing major ectopic bone formation in all cases, whereas all rabbits with an implant containing no EHDP had substantial ectopic bone formation at the end of the experiment. There was no difference between groups in the relative amount of cartilage, connective tissue, and normal bone. We conclude that local administration of EHDP may be a useful method for prevention of ectopic bone formation under the conditions and time employed.