Differences in the susceptibilities to sodium saccharin of the urinary bladder epithelium in various strains of rats and other animal species were examined. In Experiment 1, male ACI, Wistar, F344 and Sprague-Dawley rats were administered 5.0% sodium saccharin in the diet for 52 weeks. Rats were killed after weeks 12, 24, 36 and 52. In ACI rats, sodium saccharin induced not only preneoplastic lesions of the urinary bladder, but also tumors. However, in other strains it did not. The urinary bladder of ACI rats given sodium saccharin had the most marked lesions under scanning electron microscopy, with less marked changes in Wistar and F344 rats. Sprague-Dawley rats were resistant to sodium saccharin. In Experiment 2, male F344 rats, B6C3F1 mice, Syrian golden hamsters, and Hartley guinea pigs were given 5.0% sodium saccharin in the diet for 20 weeks. The animals were sacrificed sequentially. Rats developed urinary bladder lesions during the experiment, as detected by light microscopy and scanning electron microscopy. Increased DNA synthesis of the urinary bladder epithelium was detected in rats by autoradiography. However, mice, hamsters and guinea pigs were resistant to sodium saccharin. These results indicate that there are strain and species differences in the urinary bladder response to sodium saccharin.