This Phase II study was designed to determine the efficacy and tolerability of vorozole (R83842), a new nonsteroidal aromatase inhibitor, in postmenopausal women with advanced breast cancer in progression being treated with tamoxifen, and to correlate these effects with the hormonal profile and plasma drug levels. Twenty-nine eligible women with estrogen receptor-positive or unknown disease were treated with 2.5 mg vorozole once daily p.o. until disease progression. All 29 are evaluable for toxicity and 27 for response as assessed by International Union Against Cancer (UICC) criteria. After a median follow-up of 8 months, 3 patients (11%) had partial remission of their disease for 14, 15, and 16 months and 14 patients had disease stabilization for 7-24 months (median, 12). Patients with a normal carcinoembryonic antigen level (</=3 mm/liter), those without bone metastases, older women, and those with a long disease-free interval were most likely to benefit from treatment. Estradiol decreased from pretreatment levels of 9. 2-85 pm/liter (mean, 24) to below detection (9.2 pm/liter) and estrone from 64-311 pm/liter (mean, 144.3) to 19-116 pm/liter (mean, 57) after 1 month. Serum follicle-stimulating and luteinizing hormone levels rose from 9-74 IU/liter (mean, 35.3) and 3.3-38 IU/liter (mean, 17.8) to 10-102 IU/liter (mean, 44.6) and 1.6-70 IU/liter (mean, 24.2) and sex hormone-binding globulin fell from 27-138 nm/liter (mean, 65.4) to 15-109 nm/liter (mean, 53.8) after 1 month of treatment. Corresponding levels of androstenedione, dehydroepiandrosterone, free testosterone, and 17alpha-hydroxyprogesterone were unaffected. An adrenocorticotropic hormone stimulation test was normal in 18 patients 1 month after treatment commenced. Trough drug levels (measured by gas chromatography) ranged from 6.5-95 ng/ml (median, 24.5) at 1 month of treatment. Possible treatment-related side effects were mild and included malaise, anorexia and nausea, hot flashes, fluid retention, vaginal infection, alopecia, lightheadedness, and one allergic reaction which caused lip swelling. Vorozole, given orally, is a clinically active well-tolerated new treatment for breast cancer. Selective suppression of estrogen confirms its action as a specific aromatase inhibitor. Further trials to confirm its relative efficacy in postmenopausal disease and to explore its application in other settings are indicated.