We report on the potential association of suspected bisphosphonate-associated osteonecrosis of the jaw (BRONJ) recurrence with the use of the novel antiangiogenic drug sunitinib. A 59 year-old patient affected by metastatic renal cell carcinoma (RCC) and established BRONJ experienced consecutive episodes of painful jaw infection with cutaneous fistula and bone sequestration which occurred during active treatment with sunitinib, improved after discontinuation and antibiotic therapy, then rapidly worsened with resumption of sunitinib. We hypothesize that the potent antiangiogenic activity of sunitinib may amplify the inhibition of bone remodeling exerted by aminobisphosphonates entrapped within the osteonecrotic mineral matrix, antagonize mucosal healing and expose to infections during treatment. This supports the emerging role of soft-tissue damage in the pathogenesis of osteonecrosis of the jaw.