Objective: To evaluate plaque movement as a potential factor in local failure using intraoperative ultrasonography at plaque insertion and removal. Methods: Prospective study of 162 patients with uveal melanoma undergoing intraoperative B-scan ultrasonography at insertion and removal of iodine 125 plaques. Results: Tilting of the posterior plaque edge more than 1.0 mm away from the sclera was detected in 15 patients (9%) at plaque insertion and in 85 patients (53%) at plaque removal (P<.001). Factors associated with tilt at plaque removal included male sex (P=.009), decreased tumor distance to the fovea and optic disc (P<.001 for both), notched plaque (P=.001), and episcleral hematoma (P=.009). Plaque tilt caused a reduction greater than 10% in actual radiation dose to the tumor apex in 37 patients (23%). Local failure occurred in only 3 patients (2%), all of whom had tilt of 1.95 mm or greater at plaque removal. Conclusions: Plaque tilt after initial accurate placement occurs frequently during brachytherapy for uveal melanomas and may represent an important cause of local treatment failure. Recognizing and counteracting the effects of plaque tilt may reduce the risk of local failure. Trial Registration: clinicaltrials.gov Identifier: NCT00459849.