Skin carcinomas represent approximately 30% of the new cases of diagnosed cancer. Ultraviolet radiation (UV) from the sun is a major cause of non-melanoma skin cancer in humans. The prevention and mainly the photo chemoprevention with natural products represent a simple but very effective strategy in the management of cutaneous neoplasia. Objective: In this study we have investigated the effects of topical application of Calluna Vulgaris (CV) extract (1:1) in 70% ethanol to skin mice before one dose UVB irradiation on cyclobutane pyrimidine dimers (CPDs) formation, markers of oxidative stress and apoptosis. Methods: Forty-two 8-week-old female SKH-1 hairless mice were randomly divided into 6 groups: 1. group I (control) - no treatment, no irradiation; 2. group II - treated with 50 mg/cm2 hydrogel vehicle, no irradiation; 3. group III – UVB-irradiated group; 4. group IV – vehicle and UVB treated; 5. group V – CV extract treated (4 mg polyphenols/30ml/cm2), UVB irradiated; 6. group VI – CV extract incorporated in vehicle treated, UVB irradiated. UVB irradiation was performed with 240 mJ/cm2 after 30 minutes from topical application. The animals were sacrificed 24 hours after irradiation.Malondialdehyde (MDA), glutathione (GSH) and nitric oxide levels were determined in skin homogenates. CPDs were detected by immunohistochemical technique and caspase-3 activity by ELISA. Results: The treatment with CV extract inhibited UVB-induced oxidative stress (MDA: 0,76±0,04 vs. 2,81±0,94 nmoles/mg protein, p<0,001) and decreased NO levels (2,691plusmn,89 vs. 8,22plusmn3,81 nmoli/mg protein in irradiated group, p<0,0002). Topical treatment with CV before exposure to UVB inhibited CPDs formation in epidermis (56.11% vs. 90.00%) and reduced caspase-3 activity (0,37plusmn0,13 OD/mg protein vs. 0,670plusmn,14 OD/mg protein; p<0,01). Conclusion: Our results suggest that CV may be used as a novel chemo preventive candidate and possible strategy to reduce UV-induced skin cancer risk.