Summary. There is a high frequency of Leydig cell tumors associated with hypercalcemia in the aged Fischer 344 rat. We studied a transplantable tumor cell line (Rice D-6) which is associated with hypercalcemia, hypercalciuria, hypophosphatemia, renal phosphate wasting, increased urinary cyclic adenosine monophosphate (AMP) excretion, absence of bone metastases, increased osteoclastic bone resorption, and suppressed immunoreactive parathyroid hormone (iPTH) concentrations. We examined the ability of dichloromethylene diphosphonate (CI2MDP) to lower serum calcium and decrease the parameters of increased bone resorption. We used this drug also as a pharmacologic tool to determine the relationship of hypercalcemia and increased bone resorption to the abnormalities in renal tubular function associated with the humoral hypercalcemia of malignancy.Daily administration of CI.,MDP before development of hypercalcemia, in doses from 2.5-40 mg/kg body weight subcutaneously, delayed and suppressed both the hypercalcemia and hypercalciuria. There was an increase in bone mass and decrease in both osteoclast number and activity compared with bones from untreated tumor-bearing animals. The urinary hydroxyproline excretion in treated animals declined towards the normal range. There were no significant effects on serum phosphorus, urine phosphorus, or urine cyclic AMP excretion.These data suggest that C12MDP reverses the increased bone resorption that occurs in the humoral hypercalcemia of malignancy, and confirms that diphosphonates are effective agents in the prevention and treatment of increased bone resorption associated with malignant disease. They also suggest Send offprint requests to Dr. Martodam at the above address.that renal phosphate wasting and increased urinary cyclic AMP excretion are not directly related to the hypercalcemia.