Abstract Osteonecrosis is a devastating complication of long-term glucocorticoid therapy that has been described in both malignant and nonmalignant diseases. Its incidence has been found to greater than 50% using magnetic resonance imaging in asymptomatic patients, thus osteonecrosis is likely underdiagnosed. Recent studies have suggested that treatment with bisphosphonates can improve pain and mobility and decrease bone marrow edema. We describe a patient with acute lymphoblastic leukemia who presented with debilitating osteonecrosis after treatment with prednisone for a total cumulative dose of 5100 mg. Magnetic resonance imaging revealed extensive infarcts of her bilateral tibiae and femora and left humerus, talus, and calcaneus consistent with osteonecrosis that had persisted for more than 2 years. Her severe knee, shoulder, and ankle pain was treated with 1 dose zolendronic acid. Despite a prolonged acute phase reaction, the patient's symptoms improved with near total resolution of pain.