Nonmelanoma skin cancer resulting from UVB exposure is a large and growing problem in the United States. Production of reactive oxygen species (ROS) during the UVB-induced inflammatory response results in the formation of oxidative DNA adducts such as 8-hydroxy-2-deoxyguanine (8-oxo-dG), which have been shown to contribute to the development of this cancer. The 8-oxoguanine DNA glycosylase (OGG1) enzyme repairs 8-oxo-dG adducts, suggesting that enhancing its activity in the skin might increase 8-oxo-dG repair thus preventing skin cancer development. We therefore used the SKH-1 murine model to examine the effect of topically applied OGG1 on UVB-induced skin cancer development. Mice were exposed three times weekly to UVB followed immediately by topical treatment with a formulation of liposome-encapsulated OGG1 enzyme for 25 weeks. While this treatment did not affect UVB-induced tumor multiplicity, it did reduce tumor size and dramatically reduced tumor progression, as indicated by tumor grade. These results suggest that oxidative DNA damage contributes to the progression of UVB-induced skin tumors and that a topical formulation containing OGG1, perhaps in conjunction with other DNA repair enzymes such as T4 endonuclease V, could be used in populations at high risk for skin cancer development.