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The authors undertook to investigate the diagnostic performance of high-resolution ultrasound (HRUS), and to compare the differential diagnostic and staging accuracies of endoscopic ultrasonography (EUS), HRUS, and multidetector computed tomography for gallbladder (GB) polypoid lesions and GB cancer.Endoscopic ultrasonography was considered the most sensitive diagnostic modality for GB polypoid lesions. However, recent technical advancements in other image modalities including conventional sonography (US) allow the production of comparable images.A total of 170 patients, with a more than 1-cm sized polypoid GB lesion, and without evidence of definite local invasion to adjacent organs during primary screening, were consecutively enrolled in this prospective, blind, comparative study. After excluding 26 patients with inappropriate medical histories, 144 patients were finally enrolled. All patients underwent surgical resection. Clinical diagnoses were compared with histopathologic findings by diagnostic modality.Of the 144 patients, there were 115 (79.8%) cases of benign GB polypoid lesions and 29 (20.2%) cases of GB cancers. Diagnostic sensitivities for malignancy were 90% for HRUS, 86% for EUS, and 72% for CT. When evaluating the abilities of these modalities to predict GB cancer depth of invasion, we excluded 2 unusual GB malignancies (melanoma and lymphoma), HRUS was found to have the highest diagnostic accuracy of 62.9%; EUS and CT had accuracies of 55.5% and 44.4%, respectively.The diagnostic accuracies of HRUS and EUS for the differential diagnosis of GB polypoid lesions were comparable. In view of patient comfort and no requirement for sedation, we consider that HRUS is likely to become an important diagnostic modality for the differential diagnosis and staging of GB polypoid lesions and early GB cancer.