The effect of cyclophosphamide (CY) on ovarian function was studied in patients with breast cancer receiving prolonged daily administration of this agent (100 mg/day) after radical surgery. Out of 18 premenopausal patients that received 8.4-39.9 g CY, 15 developed permanent amenorrhea. The average dose given before the onset of amenorrhea was 5.2 g in patients in their 40s and 9.3 in their 30s. Urinary estrogens and serum progesterone were measured weekly for approximately 6 months postoperatively in six patients receiving CY. After the onset of amenorrhea, the levels of both hormones ceased to show their normal cyclic changes and remained low persistently, meanwhile serum FSH and LH were markedly elevated. No ovarian follicle was histologically found in three amenorrheic patients who underwent therapeutic oophorectomy after CY therapy. These findings indicate that CY induced primary ovarian failure.