Hormone therapy is often used in association with chemotherapy in the treatment of estrogen-responsive breast cancers. By using breast adenocarcinoma cell lines, we show that antiestrogen treatment leads to a dramatic decrease of p53 protein levels. This effect leads to a loss of wild-type p53 response to genotoxic treatment. This inhibition is assessed by the lack of p53 protein accumulation and the loss of the p53-dependent induction of p21(WAF1/CIP1) expression. Given that the effects of several anticancer agents are mediated through DNA damage, these observations suggest that antiestrogen treatment could modulate cellular response to chemotherapeutic agents.