The potential protective effect of a polyphenol-rich diet for colon carcinogenesis is of great scientific and medical interest. Apples are a main source of polyphenols, and apple juice has been shown to attenuate chemically induced colon carcinogenesis in animal models. In addition to an antioxidant and antiproliferative activity, apple polyphenols have been shown to elevate expression of the phase II gene glutathione S-transferase T2 (GSTT2) in colon epithelial cells. We hypothesized that apple polyphenols may thereby provide protection against oxidant-induced DNA damage. Using GSTT2 promoter constructs and luciferase reporter assays, we found that polyphenolic apple extracts (AE) can directly enhance GSTT2 promoter activity. Comet assays demonstrated that the genotoxicity of the GSTT2 substrate cumene hydroperoxide (CumOOH) was significantly reduced when HT29 colon epithelial cells were pretreated with AE. Overexpression of GSTT2 in HT29 cells significantly reduced CumOOH induced DNA damage, whereas shRNA mediated knockdown of GSTT2 gene expression resulted in higher damage. Our results causally link GSTT2 levels with protection from genotoxic stress, and provide evidence that the antigenotoxic effects of apple polyphenols in vitro are at least in part due to an induction of GSTT2 expression. Induction of phase II genes may contribute to primary chemoprevention of colon cancer by apple polyphenols.