Regorafenib is a novel, orally administered multi-kinase inhibitor that has recently been approved for the treatment of recurrent gastrointestinal stromal tumor (GIST). We report a case of successful treatment of recurrent duodenal GIST, which was found to be resistant to imatinib and sunitinib, with regorafenib. A 62-year-old woman underwent a pancreatoduodenectomy for duodenal GIST; after 2 years, a computed tomography (CT) scan detected liver metastases. The patient received imatinib for 6 years, and underwent 2 hepatectomies. Subsequently, she received sunitinib for 10 months; however, CT scans revealed the presence of multiple vertebral metastases. She underwent a laminectomy for the palliative treatment of the vertebral metastases. Upon immunohistochemical examination, the recurrent tumor stained positive for c-kit, confirming the diagnosis for GIST. Consequently, the patient received regorafenib; although the treatment controlled the liver metastases, the vertebral metastases were found to have progressed. She survived for 9 years and 5 months after the initial surgical resection. Regorafenib might be beneficial in the treatment of recurrent GISTs that prove to be resistant to imatinib and sunitinib.