Intravenous bisphosphonates reduce fracture risk but have been associated in rare cases with deteriorating renal-function in cancer patients. The renal effects of zoledronic acid were assessed in osteoporotic postmenopausal women from 27 countries who received three annual infusions of zoledronic acid or a placebo in a randomized, double-blind trial. Serum creatinine, estimated creatinine clearance and urinary protein were measured before and after at least one infusion in a predefined renal safety cohort of 5035 equally divided patients. This group was compared to 7714 patients whose parameters were measured annually. Significantly more transient pre- to post-infusion increases in serum creatinine occurred in zoledronic acid than placebo-treated patients with significant elevations, relative to pre-infusion, only in the second year. All 31 zoledronic acid and 8 of 10 patients on placebo recovered their pre-infusion serum creatinine value within 12 months. No differences in mean changes in serum creatinine, estimated creatinine clearance or adverse renal events were found. We found that transient changes in renal function can occur following an annual zoledronic acid infusion but, in the long term, renal function was not different from control patients.