Oxidative DNA modifications such as 7,8-dihydro-8-oxoguanine (8-oxoG) are generated endogenously in apparently all living cells. The defect of the repair of 8-oxoG in Csb(m/m)Ogg1⁻(/)⁻ mice results in elevated basal levels of these lesions and increased frequencies of spontaneous mutations, which initiate tumorigenesis in the liver if cell proliferation is stimulated. Here, we describe that the phytoalexin resveratrol, applied either for 7 days per gavage (100 mg/kg body wt) or for 3-9 months in the diet (0.04% ad libitum), reduces the endogenous oxidative DNA base damage in the livers of the Csb(m/m)Ogg1⁻(/)⁻ mice by 20-30% (P < 0.01). A small but consistent effect is also observed in the wild-type animals. The spontaneous mutation frequencies determined in the lacI gene of BigBlue® Csb(m/m)Ogg1⁻(/)⁻ mice are concomitantly reduced by resveratrol to similar extents. Mechanistically, the protection is caused by an induction of the antioxidant defense system since (i) hepatocytes isolated from all resveratrol-treated animals were less susceptible to the generation of single-strand breaks and to cell killing by H₂O₂, (ii) messenger RNA levels of superoxide dismutases 1 and 2 (SOD1 and SOD2) heme oxygenase-1 and glutathione peroxidase were significantly upregulated after the short-term treatment and (iii) mutations primarily ascribed to the oxidative base modification 8-oxoG (GC to TA transversions) were more strongly suppressed than GC to AT transitions ascribed to spontaneous deamination. The results thus demonstrate that spontaneous somatic mutation rates resulting from endogenous oxidative DNA damage can be reduced by application of an exogenous agent.