PURPOSE: To define computed tomography (CT) criteria for evaluating the response of patients with gastrointestinal stromal tumors (GIST) who are receiving Imatinib (tyrosine-kinase inhibitor therapy). MATERIALS AND METHODS: This prospective CT study evaluated 107 consecutive patients with advanced metastatic GIST treated with Imatinib. RESULTS: Seventy patients had total or partial cystic-like transformation of hepatic and/or peritoneal metastases. These pseudocysts remained unchanged in size or stable in size on successive CT examinations (stable disease according to RECIST criteria). Forty-six patients developed metastases, 17 patients showed increasing parietal thickness and 29 patients with peripheral enhancing nodules. These CT changes represented local recurrence consistent with GIST resistance to Imatinib treatment. WHO or RECIST criteria did not provide a reliable evaluation of disease evolution or recurrence. Development of new enhancement of lesions (parietal thickness or nodule) was the only reliable criterion. CONCLUSION: The development of peripheral thickening or enhancing nodules within cystic-like metastatic lesions, even without any change in size, represented progressive GIST under Imatinib, growing in a short time and should alert the clinician for the possible need for a change in therapy.