Increased renal uptake of 99mTc methylene diphosphonate (MDP) was observed irregularly in rats after methotrexate, vincristine or gentamicin, administered separately. Cisplatin regularly induced a dose-related increased MDP uptake which correlated with the degree of tubular damage histologically. The augmented MDP renal uptake was not consistently accompanied by a decreased clearance of simultaneously injected I-131 Hippuran, particularly at lower drug dose levels. This observation agreed with previous evidence that the mechanisms of tubular transport of diphosphonates and organic acids like Hippuran are different. At higher dose levels, the augmented MDP uptake was accompanied by increased renal calcium, hypophosphatemia, elevated serum urea nitrogen and creatinine, and only occasional, mild hypercalcemia. The magnitude of the increased renal uptake of MDP observed could not be explained by alterations in iron metabolism or by dehydration. Drug-induced renal retention of MDP by a factor of 2 or more above normal appears to be a useful indicator of tubular damage when other parameters of renal function are sometimes normal.