Reported in the literature are several cases of thromboembolic complications occurring in patients on tamoxifen citrate for metastatic breast cancer. In view of this literature, a study of patients on tamoxifen was initiated to determine if a paradoxical estrogenic effect was present as evidenced by lowered levels of antithrombin III (AT III). Both functional and immunologic levels were assayed. Twenty-four women with metastatic breast cancer (predominantly bone, 83%) on tamoxifen 10 mg by mouth twice daily were studied. The mean duration of tamoxifen therapy at the time of the AT III determination was 36 weeks (range, 2-87 weeks). The mean age of the group was 64 years with a mean functional AT III of 86% (normal, 82%-120%). Ten of 24 (42%) had low levels of functional AT III (mean, 75%), whereas, the remaining 14 (58%) had normal levels of functional AT III (mean, 94%). Immunologic AT III levels were normal in 23 patients (mean, 26 mg/dl; normal range, 17-30 mg/dl) and elevated in 1 patient. Similarly, functional and immunologic AT III levels were determined in 11 women with metastatic breast cancer on no hormonal therapy. One of 11 (9%) had a low level of functional AT III with a mean of 102% for the entire group. The mean immunologic AT III was 28 mg/dl with two elevated. The poor correlation between functional and immunologic AT III levels may be similar to the disparity noted in women using estrogen-containing oral contraceptives. The finding of lowered functional activity of AT III in 42% of tamoxifen-treated patients is preliminary in nature and will require larger confirmatory studies, including further clinical correlation of this observation.