Multiple exposures to solar ultraviolet (UV) radiation cause critical damage to skin that may lead to the development of several cutaneous disorders including skin cancer. Protection against sun-induced damage is therefore a highly desirable goal. Chemoprevention via plant-based agents may be a useful approach for the prevention? of UV-induced neoplasia. In this study, we assessed (1) whether baicalin protected against multiple UVB exposure-mediated damage in skin of C57BL/6 mice and (2) the underlying mechanisms. C57BL/6 mice were topically pretreated with baicalin (1 mg/cm(2) skin area/mouse/100 μL acetone) and were exposed to UVB 30 min later (180 mJ/cm(2), on alternate days × 10 exposures). The animals were sacrificed 24 h after the last UVB exposure. Skin edema, histopathology changes, Ki-67, PCNA, and COX-2 were assessed to determine UVB induced damage. Multiple exposures of C57BL/6 mice to UVB resulted in an increase in skin edema and hyperplasia. Topical application of baicalin prior to UVB radiation resulted in a significant inhibition of Ki-67, PCNA and COX-2 expression. These protective effects of baicalin may also inhibit UVB-induced skin carcinogenesis. Based on this data, we suggest that baicalin could be developed as an agent for the management of conditions elicited by multiple UV exposures, including skin cancer.