One hundred and forty four Fischer 344 rats and 144 B6C3F1 mice of both sexes were fed either a control diet or a diet containing 300, 600, 1200, 2400 or 3600 ppm sulfamethazine for 90 days. They were then necropsied and tissue specimens were evaluated for pathological changes by light and transmission electron microscopy. No gross or light microscopic lesions related to sulfamethazine administration were evident in the mice. Thyroid gland enlargement was evident at necropsy in one half of the rats (12 of 24) which received the 3600 ppm dosage level of sulfamethazine and in 1 of 24 rats fed the 2400 ppm level. By light microscopy, thyroid gland hyperplasia was evident in rats which received all five dosage levels of the compound, but the change was more pronounced and of a greater incidence in those administered the higher concentrations. This effect was observed in rats of both sexes but its incidence was greater in males than in females among the groups receiving the lower concentrations of compound. Ultrastructural changes included markedly dilated rough endoplasmic reticulium, altered microvilli and diminished colloid droplets involving the thyroid follicular cells and compartmentalization of colloid within the follicular lumina.