Toremifene (TOR) is a triphenylethylene derivative related to tamoxifen (TAM). TOR has antitumor activity, not dependent on estrogen receptors, and responses with TOR have been observed in patients with progressive disease during TAM-treatment. To elucidate possible cross-resistance between these two antiestrogens, we compared their anti-tumor activity in a randomized, double-blind, cross-over study. 66 postmenopausal women with advanced estrogen receptor positive or unknown breast cancer and a median age of 63 years (range 38-82) were included. Patients were randomized to TAM 40 mg/day or TOR 240 mg/day. Treatment continued until progressive disease, when cross-over to the alternative treatment was done. The response rate with first line TOR was 29% (95% confidence limits 10-41%) and with TAM 42% (95% confidence limits 25-61%). Response rates and response durations, survival and toxicity were not significantly different between the two treatments. 44 patients progressing on first line TAM or TOR were evaluable for second line TOR or TAM treatment. As no responses were observed, the possibility of over-looking a response rate of 20% or more is less than 1%. In conclusion, this study strongly indicates that TOR and TAM are clinically cross-resistant in patients with advanced breast cancer.