Two-year toxicity and carcinogenicity studies of oxytetracycline hydrochloride and tetracycline hydrochloride, two structurally similar and widely used antibiotics, were performed in F344/N rats and B6C3F1 mice. Rats and mice were continuously exposed via their diet to the following levels of antibiotic: oxytetracycline HCl--rats 0, 25,000, or 50,000 ppm; mice 0,6,300, or 12,500 ppm; tetracycline HCl--rats and mice 0, 12,500, or 25,000 ppm. On a milligram per kilogram of body weight basis these exposures represent doses that are 20 to 140 times daily human therapeutic doses. Dose-related increased survival was noted among oxytetracycline-treated male rats and tetracycline-treated female rats and male mice, while treatment-related reduced body weight gain occurred in oxytetracycline- and tetracycline-treated mice. Microscopic changes included fatty metamorphosis and focal cellular change in livers of oxytetracycline-treated male rats and basophilic cytoplasmic and clear cell change in livers of tetracycline-treated male rats. The only neoplastic changes were a marginally increased trend in pheochromocytoma of the adrenal medulla (equivocal evidence only) among oxytetracycline-exposed male rats (12/50 controls, 19/50 low dose, 24/50 high dose) and an increased incidence of pituitary adenoma or adenocarcinoma among high-dose oxytetracycline-treated female rats (20/50 controls, 32/50 high dose). Although oxytetracycline and tetracycline appeared to increase the incidence of pituitary hyperplasia in high-dose male and female rats, respectively, the total incidence of proliferative changes (hyperplasia, adenoma, and adenocarcinoma) was not affected by antibiotic exposure. The results from these studies therefore support the notion that neither antibiotic is carcinogenic in rodents. There were several negative trends suggesting possible protective effects by both these tetracycline analogs against certain spontaneous neoplastic and non-neoplastic changes.