The clinical meaning of cardiac uptake of [18F]fluorotamoxifen was assessed. Tamoxifen, a nonsteroidal antiestrogenic drug for treatment and prevention of breast cancer, has a cardioprotective, estrogen-like effect in postmenopausal women. We conducted a pilot study of [18F]fluorotamoxifen to evaluate its clinical usefulness in patients with breast cancer. Significant cardiac uptake of [18F]fluorotamoxifen in five patients was found in the pilot study. We performed positron emission tomography (PET) with [18F]fluorotamoxifen. The intracardiac distribution of [18F]fluorotamoxifen was observed and compared with the patients' clinical symptoms, past history, and results of the electrocardiogram (ECG). None of the patients had a prior history of ischemic heart disease. Various patterns of [18F]fluorotamoxifen distribution were seen in the heart: one patient showed homogeneous distribution; two had defects in the lateral wall; one had patchy distribution; and in one the uptake was questionable. Non-uniform cardiac uptake may be related to myocardial damage. Cardiac uptake of tamoxifen suggests that its cardioprotective benefits may be related not only to serum cholesterol reduction but also to a direct cardioprotective action. Further experimental studies are required to elucidate the pathophysiological mechanism of cardiac uptake of [18F]fluorotamoxifen.