Syrian hamsters were treated with diethylstilbestrol (DES), a potent estrogen and kidney carcinogen, or ethinyl estradiol (EE), a strong estrogen but weak carcinogen, for 1-9 months. At monthly intervals their kidneys were studied using light, immunoperoxidase, and electron microscopic techniques. At 5 months, DES-treated animals exhibited interstitial lesions composed of small round cells with a high nuclear:cytoplasmic ratio. Immunoperoxidase and ultrastructural studies showed these cells to be similar to cells in fully formed tumors at 9 months. Early lesions in EE-treated animals (seen as early as 1 month) were dissimilar, these lesions appeared in the deep cortex adjacent to the renal pelvis, where proximal tubules underwent hyperplastic changes, showing columnar cells with large nuclei, occasional mitoses, and sloughing of apical cytoplasm. Cells in early lesions of EE-treated animals did not resemble the fully developed tumor in either immunoperoxidase or ultrastructural features; although with longer treatment these tubular lesions progressed to dysplasia (3-5 months) and severe dysplasia/carcinoma in situ (7 months), they did not form grossly visible tumors during the 9-month study. Both early lesions identified were specific, inasmuch as they were not observed in control animals and animals treated with beta-dienestrol and 17 alpha-estradiol (noncarcinogenic weak estrogens). Animals given a combination of DES and EE showed tubular hyperplasia but not interstitial lesions; this finding was of particular interest because hamsters given this combination of estrogens do not develop gross renal tumors. These results strongly implicate the primitive interstitial cell in the hamster kidney as the cell of origin of the DES-induced neoplasm.