Palm oil is a rich source of vitamin E, carotenoids, tocotrienols and tocopherols which are natural antioxidants and act as scavengers of oxygen free radicals. 12-O-Tetradecanoyl-phorbol-13-acetate (TPA) is a known oxidant that promotes tumorigenesis in mouse skin through the elaboration of oxidative stress. In this study we therefore assessed the anti-tumor promoting potential of palm oil against TPA-mediated skin tumorigenesis in 7, 12-dimethylbenz[a]anthracene-initiated Swiss albino mice. Topical application of palm oil 1 h prior to application of TPA resulted in a significant protection against skin tumor promotion. The animals pre-treated with palm oil showed a decrease in both tumor incidence and tumor yield as compared to the TPA (alone)-treated group. Palm oil application also reduced the development of malignant tumors. Since TPA-induced epidermal ornithine decarboxylase (ODC) activity and [3H]thymidine incorporation are conventionally used markers of skin tumor promotion, we also assessed the effect of pre-application of palm oil on these parameters, and it was observed that the application of palm oil prior to the application of TPA alleviated both these TPA-induced markers of tumor promotion. The effect of pre-application of palm oil on TPA-mediated depletion in the non-enzymatic and enzymatic molecules was also assessed and it was observed that palm oil application prior to TPA application resulted in the recovery of TPA-mediated depletion in the levels of these molecules viz. glutathione, glutathione peroxidase, glutathione reductase, glutathione-S-transferase and catalase. Similarly, palm oil also exhibited a protective effect against Fe2+-ascorbate-induced lipid peroxidation in the epidermal microsomes. The results of the present study thus suggest that palm oil possesses anti-skin tumor promoting effects, and that the mechanism of such effects may involve the inhibition of tumor promoter-induced epidermal ODC activity, [3H]thymidine incorporation and cutaneous oxidative stress. © 2003 Elsevier Science Ireland Ltd. All rights reserved.