Pre-menopausal women given adjuvant chemotherapy for breast cancer experience both premature ovarian failure and loss of bone mineral density (BMD), and this study was designed to see if these observations are causally linked. Chemotherapy was administered to 41 pre-menopausal women with early breast cancer enrolled prospectively in a study of ovarian function and BMD in such women given systemic therapy. After giving written informed consent, all patients underwent baseline and regular on-treatment measurements of BMD by dual-energy X-ray absorptiometry (DXA) scan, bone turnover and ovarian function by analysis of serum hormone levels and self-reported menstrual diaries. Baseline lumbar spine BMD in the 41 women given chemotherapy was higher than the normal population (Z score 0.28 ± 0.14 (mean ± SEM), P = 0.047), and fell significantly over the first 6 months from a mean of 1.05-1.01 g/m(2), P < 0.0001, and similar but smaller changes were demonstrated in hip BMD. This fall was independent of age at diagnosis, type of chemotherapy, development of amenorrhoea or either baseline or on-treatment estradiol concentration. During the 6 months after completion of adjuvant chemotherapy, BMD fell further only in those women with low estradiol or experiencing amenorrhoea during the first 6 months, although all groups showed evidence of increased bone turnover. This study demonstrates loss of both spine and hip BMD in pre-menopausal women during 6 months' adjuvant systemic chemotherapy to be independent of changes in ovarian function. Ovarian function was, however, related to BMD changes after chemotherapy ceased.