Introduction: We report a case of acute-phase reaction of denosumab which was difficult to exclude aggravation of original cancer pain. Case: A 65 year-old man with severe pain from right back to upper abdomen due to mid thoracic vertebral metastases of small cell lung cancer was consulted to palliative care team. Denosumab 120 mg was administered subcutaneously three times every four weeks. On the next day of first administration, pyrexia occurred. At all three administrations, pain worsened for four days after the next day of administration. The pain was worsened from numerical rating scale 2 to 6. Same phenomenon was observed each time denosumab was administered for three consecutive times. Although the area of pain overlapped with that of original vertebral metastases, the repetition of the pain exacerbation soon after the denosumab administration suggested acute-phase reaction. Conclusion: Pain aggravation caused by acute phase reaction of denosumab might be overlooked in patients with cancer pain. More investigation is needed for details of acute-phase reaction caused by denosumab.