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Duodenal gastrointestinal stromal tumors (GISTs) are rare tumors which constitute < 5% of all cases of GIST. The treatment of locally advanced/inoperable and metastatic GIST is primarily tyrosine kinase inhibitor therapy (TKI), i.e., imatinib mesylate. In some patients, initial TKI therapy may result in significant downstaging of the primary tumor and metastatic disease. The role of aggressive surgical resection in such patients remains controversial. We present a case of advanced duodenal GIST treated successfully by Whipple's procedure with liver wedge resection following neoadjuvant TKI therapy. This case shows that aggressive surgical resection for metastatic duodenal GIST following neoadjuvant imatinib seems to be a feasible treatment option.