The tumor-promoting phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA) causes a dose-dependent induction (up to 300-fold) of ornithine decarboxylase activity in the epidermis of intact mice within 5 hours after the application to the skin of from 1 to 10 nmoles of the ester in 0.2 ml of acetone. Enzyme activity regresses with a half-life of 17 minutes, the shortest known for any enzyme. The induction is inhibited in a dose-dependent manner by a single application of from 0.034 to 3.4 nmoles of retinoic acid within an hour before to an hour after phorbol ester treatment. Of over thirty natural and synthetic retinoids that were tested for this property, all-trans-retinoic acid was most effective. The ability of retinoic acid and its congeners to inhibit tumor promotion by the phorbol ester correlated with the effect of dose, structure, and time of treatment on the induction of ornithine decarboxylase. It appears that a permanently increased level of the enzyme and its product, putrescine, may be one of the essential components of the mechanism of tumor promotion.