The green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) possesses promising anticancer potential. Although in vivo studies unveiled the metabolic routes and pharmacokinetics of EGCG and showed no adverse effects, in vitro studies at high concentrations demonstrated oxidative stress. EGCG causes differential oxidative environments in tumor versus normal epithelial cells, but the roles that EGCG, hydrogen peroxide (H2O2), and intracellular catalase play in the epithelial system are largely unknown. The current study employed enzyme activity assays, reactive oxygen species quantification, and immunoblotting to investigate whether EGCG-induced differential effects correlate with levels of key antioxidant enzymes and H 2O2. It was found that normal human keratinocytes with high catalase activity are least susceptible to H2O2, whereas H2O2 caused significant cytotoxicity in oral carcinoma cell lines. However, the EGCG-induced differential effects could not be duplicated by H2O2 alone. The addition of exogenous catalase failed to completely prevent the EGCG-induced cytotoxicity and rescue the EGCG-induced growth arrest in the tumor cells. The antioxidant N-acetyl-L-cysteine rescued the tumor cells from H2O 2-induced damage only, but not from EGCG-induced mitochondrial damage. Finally, alterations in catalase or superoxide dismutase activities were not observed upon EGCG exposure. In conclusion, although endogenous catalase may play a role in response to H2O2-induced cytotoxicity, the EGCG-induced cytotoxic effects on tumor cells mainly result from sources other than H2O2.