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Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the intestinal tract. Nearly all tumors have an activating mutation in the KIT or, less often, PDGFRα, gene. Therapy with tyrosine kinase inhibitors benefits over 80% of patients with advanced GIST, but most patients eventually develop drug resistance.Forty patients with metastatic GIST were treated with tyrosine kinase inhibitors and then underwent surgical resection. Based on the growth of their tumors by serial radiologic imaging, patients were categorized at the time of operation as having responsive disease, focal resistance (1 tumor growing), or multifocal resistance (more than 1 tumor growing). Patients were followed for a median of 15 months (range, 6–46 months) after surgery.Initially, molecular therapy achieved stable disease or a partial response in all but 1 patient. Surgery was performed after a median of 15 months, and there were no perioperative deaths. After operation, the 20 patients with responsive disease had a 2-year progression-free survival of 61% and 2-year overall survival of 100%. In contrast, the 13 patients with focal resistance progressed after surgery at a median of 12 months and the 2-year overall survival was 36%. There were 7 patients with multifocal resistance and they progressed postoperatively at a median of 3 months and had a 1-year overall survival of 36%.Selected patients with metastatic GIST who have responsive disease or focal resistance to tyrosine kinase inhibitor therapy may benefit from elective surgical resection. Surgery for patients with metastatic GIST who have multifocal resistance is generally not indicated, and these patients should be considered for clinical trials of new systemic agents.