OBJECTIVES Bisphosphonates have been used successfully in the treatment of hypercalcemia and to reduce skeletal-related complications of bone metastases. Recent in vitro and in vivo evidence suggest that they may also have direct antitumor effects via induction of apoptosis, inhibition of the invasive potential of tumor cell lines in vitro, inhibition of angiogenesis, and reduction in tumor growth indirectly via effects on accessory cells. This is a randomized, open label, prospective study that examined the effect of preventive zoledronic acid treatment on the development of bone metastases in patients with recurrent solid tumors, without bone metastases at the time of randomization. METHODS Forty patients with recurrent or metastatic advanced cancer, without bone metastases, were randomized into the trial to either receive zoledronic acid or no treatment. Patients were followed up until bone metastases were established. RESULTS The percentage of patients being bone metastases free at 12 mo was 60% in the zoledronic acid and 10% in the control group (p<0.0005), while the percentages at 18 mo were 20% and 5% respectively (p=0.0002). CONCLUSIONS The results have shown that bisphosphonates as adjuvant treatment might be useful for the prevention of bone metastases; however, there is need for blinded randomized data before such an approach would be confirmed. In the meantime preventive use of bisphosphonates in patients without any bone metastases should not be used outside the scope of a clinical trial.