OBJECTIVE: To evaluate the frequency, risk factors, and clinical presentation of bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ). STUDY DESIGN: We performed a retrospective analysis of 576 patients with cancer treated with intravenous pamidronate and/or zoledronate between January, 2003 and December, 2007 at the University of Minnesota Masonic Cancer Center and Park Nicollet Institute. RESULTS: Eighteen of 576 identified patients (3.1%) developed BRONJ including 8 of 190 patients (4.2%) with breast cancer, 6 of 83 patients (7.2%) with multiple myeloma, 2 of 84 patients (2.4%) with prostate cancer, 1 of 76 patients (1.3%) with lung cancer, 1 of 52 patients (1.9%) with renal cell carcinoma, and in none of the 73 patients with other malignancies. Ten patients (59%) developed BRONJ after tooth extraction, whereas 7 (41%) developed it spontaneously (missing data for 1 patient). The mean number of BP infusions (38.1 +/- 19.06 infusions vs. 10.5 +/- 12.81 infusions; P<0.001) and duration of BP treatment (44.3 +/- 24.34 mo vs. 14.6 +/- 18.09 mo; P<0.001) were significantly higher in patients with BRONJ compared with patients without BRONJ. Multivariate Cox proportional hazards regression analysis showed that diabetes [hazard ratio (HR)=3.40; 95% confidence interval (CI), 1.14-10.11; P=0.028], hypothyroidism (HR=3.59; 95% CI, 1.31-9.83; P=0.013), smoking (HR=3.44; 95% CI, 1.28-9.26; P=0.015), and higher number of zoledronate infusions (HR=1.07; 95% CI, 1.03-1.11; P=0.001) significantly increased the risk of developing BRONJ. CONCLUSIONS: Increased cumulative doses and long-term BP treatment are the most important risk factors for BRONJ development. Type of BP, diabetes, hypothyroidism, smoking, and prior dental extractions may play a role in BRONJ development.