A single application of 17 nm of 12-O-tetradecanoyl-phorbol-13-acetate (TPA) onto the backs of CD-1 female mice results in a significant increase in epidermal wet weight and protein, which reaches its peak by 2 days, remains high for the next two days, and then begins to decrease, reaching normal levels by 10 days. This increase in epidermal mass is brought about largely by an increase in cell number, as evidenced by increases in the total amount of DNA, the number of nucleated cell layers, and the total number of epidermal nuclei/mm of interfollicular epidermis (IFE). The increase in the total number of epidermal nuclei/mm IFE is due entirely to an increase in the number of suprabasal nuclei/mm IFE. The number of basal nuclei/mm IFE actually is reduced by 50% by Day 1, remains low for the next 2 days, and then slowly increases back to normal levels by Day 10. Histologic examination indicates that at Days 1 and 2, when there is a significant decrease in the number of basal cells, there is marked epidermal cell damage. During this time, mitotic activity of the basal epidermal cells increases significantly, reaching a peak of 19 X that above normal by Day 2, and then slowly returns toward normal levels by Day 10. Our results suggest that the epidermal hyperplasia produced by 17 nm of TPA is probably a regenerative epidermal hyperplasia.