The disposition of tiludronate in mouse, rat, rabbit, dog and monkey has been studied after oral and intravenous doses. Like other bisphosphonates, tiludronate was characterized by poor absorption from the gastrointestinal tract. Peak plasma concentrations appeared shortly (0.5-1 h) after dosing, except for the baboon (4.5 h). Food intake highly impaired intestinal absorption The affinity of tiludronate for bone and the slow release from this deep compartment could account for the large volume of distribution and the low plasma clearance found in all species. Tiludronate has low affinity for red blood cells and binds moderately to serum proteins, mainly to serum albumin. Calcified tissues appeared to be the main target for deposition. Distribution into bone was not homogenous, with higher levels in the trabecular bone than in the corticol part of the long bones. The uptake of tiludronate into bone was unequivocally less in the older animal. No metabolism occurred in the tested animal species. The major route of elimination of the absorbed drug is urine. Preclinical observations made with tiludronate, like with other bisphosphonates, were predictive of results obtained in clinical investigation.