The chemopreventive effect of Withania somnifera hydroalcoholic root extract (WSRE) on 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin cancer was investigated in Swiss albino mice. The skin lesions were induced by the twice-weekly topical application of DMBA (100 nmol/ 100 microliters acetone) for 8 wk on the shaved back of mice. WSRE was administered at the maximal tolerated dose of 400 mg/kg p.o. three times per week on alternate days 1 wk before DMBA and continued for 24 wk thereafter. The results of the study revealed a significant decrease in incidence and average number of skin lesions in mice compared with DMBA alone at the end of Week 24. Biochemical parameters were assessed in the lesions of WSRE-treated and untreated control mice. A significant impairment was noticed in the levels of reduced glutathione, malondialdehyde, superoxide dismutase, catalase, glutathione peroxidase, and glutathione S-transferase in skin lesions of DMBA-treated control mice compared with vehicle-treated mice. These parameters were returned to near normal by administration of WSRE to DMBA-treated mice. The above findings were supported by histopathological studies. From the present study, it can be inferred that WRSE possesses potential chemopreventive activity in this experimental model of cancer. The chemopreventive activity may be linked to the antioxidant/free radical-scavenging constituents of the extract. The anti-inflammatory and immunomodulatory properties of WSRE are also likely to contribute to its chemopreventive action.