An animal model is described to test the effect of diphosphonates, which are powerful antiosteolytic agents, against bone tumors. This model consists of injecting Walker tumor cells into one iliac artery of a series of rats while the contralateral artery is clamped during the injection, and waiting 7 days to obtain a significant destruction of the femur and tibia of the rats. In most of the animals, after this delay, extensive lesions are observed macroscopically by X-ray and histologically. The parenteral administration of three diphosphonates, dichloromethylene diphosphonate, ethanehydroxydiphosphonate , and aminopropanediphosphonate , at 16 and 160 mumol/kg/day, protects the bones by decreasing the extent of osteolysis. This protective effect is seen both in the tumor-injected leg and in the contralateral leg and is significant when compared to nontreated animals. The most active of the drugs was dichloromethylene-diphosphonate; ethanehydroxydiphosphonate and aminopropanediphosphonate were less active, especially when given at the higher dosage. All diphosphonates produce a marked decrease of the number of osteoclasts; ethanehydroxydiphosphonate at the higher dosage, induced a large increase of nonmineralized bone. These results are discussed in light of recent clinical work, showing that this animal model is a useful tool to test the effect of new drugs against osteolysis of cancer.