The protective effect of fruit and vegetables against cancer has been related to their high antioxidant content. However, results from intervention trials have not been conclusive on the protective effect of antioxidant supplementation. In a randomized placebo-controlled trial we investigated the effect of dietary supplementation with antioxidants on a biomarker of oxidative DNA damage with mechanistic relation to carcinogenesis. One hundred forty-two smoking men aged 35-65 y were randomly assigned to one of the following seven treatments for 2 mo: 100 mg D-alpha-tocopheryl acetate plus 250 mg slow-release ascorbic acid twice a day (n = 20), 100 mg D-alpha-tocopheryl acetate twice a day (n = 20), 250 mg ascorbic acid twice a day (n = 21), 250 mg slow-release ascorbic acid twice a day (n = 21), 30 mg coenzyme Q10 in oil three times a day (n = 20), 30 mg coenzyme Q10 as granulate three times a day (n = 20), or placebo twice a day (n = 20). The trial outcome was the urinary excretion rate of 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-oxodG)-a repair product of oxidative DNA damage. Two months of supplementation did not result in significant changes in the urinary excretion rate of 8-oxodG in any group. The lack of effect of antioxidant supplementation on the excretion rate of 8-oxodG, despite substantial increases in plasma antioxidant concentrations, agrees with the results from recent large intervention studies with cancer as an endpoint. The cancer-protective effect of fruit and vegetables seems to rely not on the effect of single antioxidants but rather on other anticarcinogenic compounds or on a concerted action of several micronutrients present in these foods.