Vitamin C is present in high concentrations in cells and body fluids and it is straightforward to assume that it could prevent oxidation of important macromolecules such as DNA. This chapter focuses on the scientific data available about the relationship between oxidative DNA damage and vitamin C, including whether vitamin C can act as an antioxidant as well as a prooxidant in vivo. There is a generally accepted concept that changes in DNA are necessary but not sufficient for cancer development. Vitamin C has been called the most important water soluble antioxidant in plasma and its antioxidant properties both in vitro and in vivo have been documented extensively. The chapter describes that there are surprisingly few intervention trials with vitamin C with regard to prevention of cancer or its surrogate markers. It concludes that the methodology for using surrogate endpoints and surrogate tissue is still in its infancy and that much development is needed.