Antioxidants have been shown to provide protection against carcinogens, toxic xenobiotics and oxidative stress. This has led to the hypothesis that the addition of antioxidants to cancer chemotherapeutic regimens could increase their efficacy while reducing the side effects often encountered during treatment. The work described in this study set out to test this hypothesis using two different chemotherapeutics, Paclitaxel and FUdR, and three different antioxidants, epigallocatechin gallate, phenethyl isothiocyanate and tert-butylhydroquinone. Experiments were carried out on two different breast carcinoma cell lines, MCF-7 and MDA MB435S. Importantly, we did not observe an enhancement of the efficacy of the chemotherapeutic agents in the twelve combinations tested. In fact, for several combinations, simultaneous treatment with an antioxidant attenuated the efficacy of the chemotherapeutic agent. We also determined that the survival advantage provided by antioxidants is consistent with their ability to induce the expression of genes whose regulatory regions contain antioxidant response elements. Together, these findings suggest that the simultaneous use of antioxidants and chemotherapeutic agents has the potential to attenuate the efficacy of chemotherapy by inducing the expression of enzymes that can detoxify cytotoxic agents. In view of these findings, we suggest that the design of chemotherapeutic regimens that combine antioxidants with chemotherapeutic agents should be considered carefully before being initiated.