The aims of this study were to determine the effects of the bisphosphonate, clodronate, on the incidence of skeletal metastases and associated morbidity in women with advanced breast cancer. 133 women with recurrent breast cancer, but no evidence of skeletal metastases, were randomly allocated to receive clodronate 1600 mg daily by mouth or an identical placebo for 3 years under double-blind conditions at two clinical oncology centers in the UK and Canada. Main outcome measures included the occurrence of skeletal metastases, as judged by sequential bone scans and radiographs, and the morbidity associated with skeletal metastases comprising the incidence of hypercalcemia, vertebral, and nonvertebral fractures, and bone pain assessed by the requirements for skeletal radiotherapy. The number of patients developing skeletal metastases was lower in clodronate-treated patients than with placebo (15 vs. 19), but was not significantly different. The number of skeletal metastases was significantly lower with clodronate treatment than with placebo (32 vs. 63; p < 0.005). The complications of skeletal disease were fewer by 26% in clodronate-treated patients compared to controls (p < 0.01). Compared to placebo, significant effects in favor of clodronate were observed for vertebral deformities (29%) and nonvertebral fractures (75%), but the event frequency of each was low. There was a small (22%) but nonsignificant treatment effect on the requirements for radiotherapy and hypercalcemia (39%). There was no effect of clodronate on survival. We conclude that clodronate by mouth significantly decreases the number and complications of skeletal metastases in women with advanced breast cancer.