A rapidly growing list of hydrocarbons has been reported to induce morphological changes in the kidney of adult male rats, beginning with hyaline droplet accumulation (HDA) followed by the development of granular casts, later on chronic nephrosis as sequela, and finally renal adenomas and carcinomas. The present study focuses on identifying structure-based properties common to HDA-inducing aliphatics and cycloaliphatics. On the basis of rank-ordered activities reported in the literature, a calculated n-octanol-water partition coefficient above 3.5 and the presence of an isopentyl structural moiety appear to be associated with HDA-inducing activity in aliphatics. A binding site model for highly active aliphatics has been derived by superimposing their minimum energy conformations along the common isopentyl substructure and calculating the union volume of their respective van der Waal (VDW) volumes. Generalization of this model to include cycloaliphatics has been achieved by maximizing the steric overlap of the VDW volumes of the compounds with their binding site union volume. HDA-inducing cycloaliphatics are correctly identified on the basis of their negligible excess volume. This approach has been used to predict the HDA-inducing activity of previously untested compounds. Eighteen aliphatic/cycloaliphatic hydrocarbons were screened in a study on adult male Wistar rats treated with 250 mg/kg per day for 5 days. Azan-stained kidney sections were semiquantitatively evaluated for the presence of HDA. The predicted and observed HDA activities were in very good agreement.