Ethylene-1-hydroxy-1, 1-diphosphonate (EHDP) was administered intraperitoneally to one-day old rats at a concentration of 30 and 40 mg/kg body weight/injection. Two groups of animals received four doses, respectively, over a 44-hour-period and a third group received two high doses with a 15-hour interval, the total amounts corresponding to 30, 40 and 20 mg/P/kg body weight. Animals in the first two experimental groups showed increased width of the hypertrophic zone as compared with normal controls and lack of calcified septa within the zone of provisional calcification. In the calcification zone, persistent atypical chondrocytes were present and in the septa a large number of matrix vesicles which hardly ever contained any crystals. The ground substance of these septa contained fine precipitates, probably representing proteoglycan complexes which were not seen normally in this zone. In the third group, the septa of the calcification zone were calcified and the hypertrophic zone was not clearly widened. In the metaphysis, remnants of cartilage or osteoid were observed as "islands" covered with osteoblast-like cells which showed signs both of collagen and apatite formation, the latter evidenced by the appearance of crystals within the matrix vesicles. It is suggested that the complex effects observed in calcifying cartilage after administration of high doses of EHDP in vivo are not restricted solely to the stage of crystal formation.