In order to determine the usual dose in the first line therapy and a high dose in the second or third line therapy, a dose finding study of a novel antiestrogen NK 622 (toremifene citrate) was performed in patients (pts) with advanced or recurrent breast cancer. NK 622 was orally administered daily once for more than 8 weeks. In pts without previous drug therapy or in pts with cancer relapse after adjuvant therapy, the response rates [(CR + PR)/total] were 24.1% (7/29), 13.8% (4/29), 20.0% (1/5) and 40.0% (2/5) at doses of 40, 60, 120 and 240 mg/day, respectively. A 40 mg/day dose showed an objective response only in postmenopausal pts with estrogen receptor (ER) positive or unknown cancer. At a dose of 60 mg/day, some of the responding cases were premenopausal pts or pts with ER(-) cancer. In pts with cancer relapse during adjuvant therapy or in those with previous therapy and/or radiation, response rates were 25.0% (2/8), 0% (0/4), 13.5% (5/37) and 10.3% (4/39) at doses of 40, 60, 120 and 240 mg/day, respectively. Response was more frequent in pts with ER (+) cancer than with ER (-) cancer. The response rates in pts with previous therapy including tamoxifen (TAM) except medroxyprogesterone (MPA) were 14.3% (4/28) at a 120 mg/day dose and 6.1% (2/33) at a 240 mg/day dose. In pts with previous therapy including TAM, MPA and other antitumor agents, the rate was 18.2% (2/11) at a 120 mg/day dose. Side effects such as elevation of GOT, GPT and serum Ca level, decrease of hemoglobin, anorexia, nausea/vomiting, fatigue, dizziness and hot flush were observed. These side effects were moderate in grade and reversible. Dose dependency of side effects was not clearly observed in grade and incidence. From these results, NK 622 is expected to be a safe drug with efficacy in first line therapy at a dose of 40 mg/day and in second or third line therapy at a dose of 120 mg/day.