Bisphosphonates are recommended in patients with osteolytic lesions secondary to multiple myeloma. We report on the safety of bisphosphonate therapy with long-term follow-up in the Medical Research Council Myeloma IX study. Patients with newly diagnosed multiple myeloma were randomised to zoledronic acid (ZOL; 4 mg intravenously every 21–28 d) or clodronate (CLO; 1600 mg/d orally) plus chemotherapy. Among 1960 patients (5·9-year median follow-up), both bisphosphonates were well tolerated. Acute renal failure events were similar between groups (ZOL 5·2% vs. CLO 5·8% at 2 years; incidence plateaued thereafter). The overall incidence of confirmed osteonecrosis of the jaw (ONJ) was low, but higher with ZOL (ZOL 3·7% vs. CLO 0·5%; P < 0·0001). ONJ events were generally low grade and most occurred between 8 and 30 months (median time to ONJ, 23·7 months). Among 10 patients with ONJ recovery data, four patients in the ZOL group completely recovered, two patients improved, and three patients experienced no improvement; one CLO patient experienced no improvement. Dental surgery or trauma preceded ONJ in six ZOL patients. The incidence of renal adverse events was similar for ZOL and CLO. ONJ incidence remained low and was lower with CLO compared to ZOL. We have seen no further ONJ cases to date.