Tamoxifen is a nonsteroidal anti-oestrogen with gynaecological side-effects. Only recently, ovarian cyst formation during tamoxifen treatment has been reported. The present study aimed to evaluate patient-related parameters that determine ovarian cyst formation in women using tamoxifen for breast cancer. A cross-sectional study was performed in 142 breast cancer patients using tamoxifen. Forty-five patients were also examined prior to tamoxifen treatment. Gynaecological assessment, transvaginal ultrasonography (TVU) and serum oestradiol (E2) and follicle stimulating hormone (FSH) analysis were performed. Follow-up assessments were performed twice a year. Uni- or bilateral ovarian cysts were detected by TVU in 24 tamoxifen-using patients and in one patient before tamoxifen treatment. Multiple regression analysis showed that cyst development is related (multiple R = 0.73) to high E2 (P < 0.001), younger age (P < 0.001) and absence of high-dose chemotherapy (P = 0.007). Patients with ovarian cysts had higher serum E2 levels compared to patients without cysts (1.95 vs 0.05 nmol l(-1); P < 0.001). All patients after high-dose chemotherapy or older than 50 years had E2 < 0.10 nmol l(-1) and/or amenorrhoea > 1 year and did not develop ovarian cysts. Patients still having a menstrual cycle during tamoxifen had a high chance (81%) of developing ovarian cysts. Breast cancer patients receiving tamoxifen only develop ovarian cysts if their ovaries are able to respond to FSH stimulation as shown by E2 production.