We have shown previously that Vitamin E acts as a tumor promoter in 7,12-dimethylbenz(a)anthracene (DMBA) initiated mouse skin. We now show that high concentrations (80 micromol) of Vitamin E are required for promotion, and that 10-fold lower concentrations do not promote tumor formation. The same high concentration of the water-soluble anti-oxidant Vitamin C did not act as a tumor promoter, but did amplify the promoting effect of high, but not low, concentrations of Vitamin E. Oxidizing free radicals generated by beta-radiation exposure of the skin at the time of Vitamin E treatment also enhanced promotion by high (but not low) concentrations of Vitamin E. The results are consistent with a process whereby tumor promotion by the lipid-soluble Vitamin E occurs as a result of alpha-tocopherol acting as a free radical scavenger, with the formation and subsequent transfer of the alpha-tocopherol free radical center to the surrounding lipids, resulting in lipid oxidations.