The incidence, characteristics and risk factors for the development of osteonecrosis of the jaw (ONJ) were evaluated among 303 myeloma patients. Only patients who received bisphosphonates developed ONJ (28/254; 11%). Zoledronic acid produced 9.5-fold greater risk for developing ONJ than pamidronate alone (P = 0.042) and 4.5-fold greater risk than subsequent use of pamidronate + zoledronic acid (P = 0.018). Use of thalidomide and number of bisphosphonate infusions also increased the risk for ONJ by 2.4-fold (P = 0.043), and 4.9-fold respectively (P = 0.012). ONJ developed earlier among patients receiving zoledronic acid. Our data indicates that administration of zoledronic acid for more than 2 years or in combination with thalidomide requires caution in myeloma.