In this study, we tested the hypothesis that heat shock proteins (hsps) 27 and 70 are associated with clinical resistance to tamoxifen. hsp27 is, like progesterone receptor, an estrogen-regulated protein. hsp70 is also of interest because of its interaction with estrogen receptors and because hsp70 is a component of the molecular chaperone machinery functioning in the assembly and trafficking of steroid receptors. In addition, hsps in general help protect cells against noxious stimuli and stress, and their expression has been linked to drug resistance. The study involved 205 tumors from estrogen receptor-positive tamoxifen-treated breast cancer patients with metastatic disease. All patients received daily tamoxifen as initial therapy for metastatic disease. The study began in 1982, and follow-up is now 9 years. hsp27 and hsp70 were detected by immunohistochemistry and scored according to the nuclear and/or cytoplasmic content. Expression of hsp27 or hsp70 was unrelated to estrogen receptor content, progesterone receptor content, menopausal status, age, and presence of visceral disease. Cytoplasmic and nuclear hsp27 positivities were weakly and inversely related to each other (P = 0.05). There was a significant association between cytoplasmic hsp27 and cytoplasmic hsp70 content (P < 0.001), as well as between nuclear hsp70 and nuclear hsp27 content (P = 0.001). Cytoplasmic and nuclear hsp70 were also associated (P = 0.02). However, increased hsp27 and hsp70 expression (nuclear or cytoplasmic) was not significantly associated with response to tamoxifen, time to treatment failure, or survival. Thus, this study clarifies the lack of clinical utility of hsp27 and hsp70 in predicting the response to tamoxifen in an estrogen receptor-positive breast cancer population.