Purpose Bisphosphonates (BPs) effectively treat metastatic bone disease, hypercalcemia, and osteoporosis. BP exposure, however, may be associated with osteonecrosis of the jaw (ONJ). The aim of the present study was to estimate the magnitude of the association between intravenous (IV) BP exposure and ONJ, and to identify potential confounders. Materials and Methods Using a case-control study design, the investigators identified and adjudicated a sample of cases with ONJ and matched them randomly with 5 controls per case. The controls were matched to cases on age, gender, cancer type, and date of cancer diagnosis. The medical records were abstracted and data on BP exposure, cancer therapy, and comorbidities were recorded. Statistical analyses were carried out using conditional logistic regression in Stata 9.0 (Stata Corp, College Station, TX). Results Thirty cases of ONJ were identified at Massachusetts General Hospital from February 2003 through February 2007. Zoledronate was found to confer significant risk toward development of ONJ (adjusted odds ratio = 31.8, P < .05). Although a trend toward increased risk was noted for pamidronate, this association was not significant after controlling for zoledronate. Obesity and smoking were associated significantly with ONJ development, whereas oral BPs had no effect. Conclusion In this study, cancer patients who had received zoledronate exhibited a significant 30-fold increase in their risk to develop ONJ. More studies are needed to elucidate the exact role of obesity and smoking in the development of ONJ, and the complex interactions of IV BPs with other chemotherapies during cancer treatment.