The use of dietary botanicals is receiving considerable interest in the protection of skin from the adverse biological effects of solar ultraviolet (UV) radiation. Dietary feeding of proanthocyanidins extracted from grape seeds (GSP) (0.2 and 0.5%, w/w) in AIN76 control diet to SKH-1 hairless mice resulted in prevention of photocarcinogenesis in terms of tumor incidence (20-95%), tumor multiplicity (46-95%) and tumor size (29-94%) against UVB-induced complete (both initiation + promotion), initiation and promotion stages of photocarcinogenesis. Feeding of GSP (0.5%, w/w) also resulted in prevention of malignant transformation of UVB-induced papillomas to carcinomas in terms of carcinoma incidence (45%), carcinoma multiplicity (61%) and carcinoma size (75%) compared with non-GSP treated mice following UVB-induced complete carcinogenesis protocol at the end of 30 weeks. Biochemical analysis revealed that treatment of GSP in vivo and in vitro systems significantly inhibited UVB- or Fe3+-induced lipid peroxidation by 57-66% (P < 0.01) and 41-77% (P < 0.05-0.001), respectively, thus suggesting the antioxidant mechanism of photoprotection by GSP. Long-term feeding of GSP did not show apparent signs of toxicity in mice when determined in terms of body weight, diet consumption and physical characteristics of internal body organs like spleen, liver and kidney. Feeding of GSP also did not show apparent signs of toxicity when determined in terms of total body mass (mass of lean + fat), total bone mineral density and total bone mineral content by employing dual-energy X-ray absorptiometry (DXA). DXA analysis also revealed that feeding of GSP significantly decreased tissue fat level (24-27%, P < 0.05) without changing the total body mass of the animals compared with non-GSP-fed animals. This can be attributed to increased lipolysis or decreased synthesis of fat due to administration of GSP. Together, it can be suggested that inhibition of photocarcinogenesis by GSP treatment may be associated with the reduction in UVB-induced oxidative damage and tissue fat content.