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To explore the role of surgery of residual disease following a period of therapy with imatinib mesylate in advanced gastrointestinal stromal tumors (GIST).From January 2001 to June 2005, 159 patients with advanced/metastatic GIST were treated with imatinib mesylate at a single institution. As of June 2002, 38 patients were selected for surgery following a variable period of imatinib therapy. Twenty-seven patients were operated on while they were in response, 8 in progression, 3 for localized disease. Clinical, pathologic, and molecular features were assessed and are reported.Postsurgery PFS was 96% at 12 months and 69% at 24 months for responding patients, while it was nil at 12 months for progressing ones. Disease-specific survival at 12 months was 100% for responding patients and 60% for progressing ones. In responding cases, secondary progression was mainly related to postsurgical imatinib discontinuation, irrespective of pathologic or molecular variables. In progressing patients, secondary resistance was mainly related to acquired mutations.In advanced GIST patients who are responding to imatinib mesylate, the role of surgery is not formally demonstrated at the moment, but this option may well be considered investigational, or suitable for an individualized decision-making in the lack of evidence. In our series, patients progressing on imatinib mesylate did not seem to have any major benefit from surgery, although their number is low.