E-3',3",5',5"-Tetrafluorodiethylstilbestrol (TF-DES), a structural analogue of diethylstilbestrol synthesized as a possible noncarcinogenic estrogen, was found to induce renal clear-cell carcinoma in Syrian hamster. The tumor induction frequency of TF-DES was the same as that of diethylstilbestrol, although the induction period was longer (approximately 9 months) than that of diethylstilbestrol (approximately 6 months). TF-DES was estrogenic and was found to support in vivo growth of estrogen-dependent H-301 cells, a cell line derived from the primary estrogen-induced and -dependent renal clear-cell carcinoma of male Syrian hamster. These data established the ability of TF-DES not only to induce tumors but also to promote estrogen-dependent tumor growth after the initiation process. Oxidation of TF-DES to TF-DES quinone was catalyzed by horseradish peroxidase. The structure of this metabolic intermediate was confirmed by comparison with synthesized TF-DES quinone. This intermediate was very unstable (half-life in methanol, 24 min; half-life in water, 4 min) and rearranged to Z,Z-3',3",5',5"-tetrafluorodienestrol. Based on the experiments with the fluorinated derivative, it is postulated that stilbestrol estrogens induce tumors via metabolic oxidation to quinone intermediates, which then may interact with DNA or other cellular targets.