The knee is the second most common site of osteonecrosis (ON) after the hip. Three different entities are described: a) spontaneous ON; b) secondary ON; c) post-arthroscopy ON. In spontaneous ON the etiology is attributed to subchondral insufficiency fractures and to avascular necrosis due to ischemic events. Diagnosis is based on clinical and radiological basis (radiography, bone scan scintigraphy and MRI). Koshino´s radiological classification grades severity and guides in the management. Conservative management includes protected weight bearing, drugs (NSAIDs, bisphosphonates, D vitamin, calcium, prostaglandin I-2, corticosteroids, hyaluronic acid), physiotherapy (laser, pulsed electromagnetic fields), and hyperbaric oxygen therapy. Surgical treatment is deserved for advanced stages or if conservative treatment failed. In pre-collapse Stage, joint preserving procedures are expected; on the contrary, in subchondral collapse stages, joint arthroplasty is required. We present for the first time in literature the beneficial effect of intra articular ozone in the management of two cases of advanced ON of the knee.