Free radical generating compounds have been shown to enhance the malignant conversion of papillomas to carcinomas in mouse skin, and iron has been shown to participate in free radical generating reactions. In the present study, we investigated whether iron can play a role in the malignant conversion of papillomas to carcinomas. Skin tumors were chemically induced in female Swiss albino mice using a standard two-stage initiation-promotion protocol. Topical application of 12-O-tetradecanoyl phorbol 13-acetate (TPA), benzoyl peroxide (BPO), H2O2 and cumene hydroperoxide (COOH) to these tumor-bearing mice increased the rate of malignant conversion. To evaluate the effect of iron-overload on the conversion of benign skin papillomas to carcinomas, the animals were pre-treated with 1.0 mg Fe per mouse for 15 days before they received TPA or free radical generating compounds. The number of carcinomas and the percent incidence of carcinomas were recorded weekly. The rate of malignant conversion was higher in iron-overloaded mice as compared with non-iron-overloaded mice. The ability of iron-overload in enhancing the malignant conversion was in the order TPA < BPO < H2O 2 < COOH. Iron was the most effective in enhancing COOH-mediated malignant transformation. Inorganic peroxide (H2O2)- mediated malignant transformation was also enhanced effectively by iron. This may be because a combination of iron accessibility and H2O 2 results in the formation of the very reactive hydroxyl radical via the Fenton reaction, which can cause DNA damage. Besides this, the cutaneous iron levels were also higher in iron-overloaded mice as compared with non-iron-overloaded mice. Histopathological sections of tumors also showed a higher degree of keratinization and pearl formation in iron-overloaded animals. Thus, we observe that in iron-overloaded animals, free radical generating agents bring about the rapid progression of benign mouse skin papillomas to carcinomas. © Springer-Verlag 2003.