Free radical generating organic peroxides and hydroperoxides are known to promote tumors in mouse skin and iron has been shown to participate in free radical generating reactions. In the present study, we have used various peroxides and hydroperoxides as stage-I and -II tumor promoters and have studied the effect of iron-overload on the two stages of tumor promotion. Swiss albino mice were iron-overloaded by injecting iron-dextran (1.0 mg Fe/mouse per day for 15 days). Twenty-four hours after the last injection of iron-dextran, the animals were initiated with 40 μg 7,12 dimethylbenz[a]anthracene. One week following initiation stage-I tumor promotion was accomplished by applying 12-O-tetradecanoyl phorbol-13-acetate (TPA), benzoyl peroxide (BPO), cumene hydroperoxide (COOH) or H2O2 to mice twice weekly for 2 weeks. Stage-II tumor promotion was accomplished by applying mezerein, BPO, COOH or H2O2 to these mice twice weekly for 40 weeks. The appearance of the first papilloma and the number of tumors/mouse were recorded weekly. When compared to non-iron-overloaded mice, the iron-overloaded mice showed a higher tumor incidence and number of tumors/mouse. The order in which iron-overload was effective in increasing tumor promotion by stage-I tumor promoters was H2O2>COOH>BPO>TPA and the order in which iron-overload was effective in increasing tumor promotion by stage-II tumor promoters was COOH>mezerein>BPO. Induction in ornithine decarboxylase (ODC) activity, [3H]thymidine incorporation in cutaneous DNA and cutaneous lipid peroxidation were also higher in the iron-overloaded mice. TPA was the most effective in inducing epidermal ODC activity and [3H]thymidine incorporation followed by mezerein, COOH and BPO. In addition, the level of epidermal reduced glutathione and the activities of antioxidant enzymes were lower in iron-overloaded mice. Besides this, cutaneous iron levels were higher in iron-overloaded mice. Thus, we conclude from this study that iron-overload augments stage-I and stage-II of tumor promotion in murine skin. © 2002 Published by Elsevier Science Ireland Ltd.