To describe the principal histopathologic findings in a series of 1,527 globes with uveal melanoma and the relationship of these findings to each other. All eyes enucleated in the Collaborative Ocular Melanoma Study (COMS) were examined independently by three ophthalmic pathologists and the findings recorded on a data form. A composite of findings was obtained after adjudication. The diagnosis was choroidal melanoma in 1,527 (99.7%) of 1,532 cases examined. Misdiagnoses were metastatic adenocarcinoma (four) and hemangioma (one). Spindle cell (9.0%), mixed cell (86.0%), and epithelioid cell (5.0%) types were observed. Medium tumors were located more posteriorly than large tumors. Considerable local invasion was seen: rupture of Bruch's membrane (87.7%), invasion of the retina (49.1%), tumor cells in the vitreous (25.2%), vortex vein invasion (8.9%), invasion of tumor vessels by tumor cells (13.8%), and invasion into emissary canals (55.0%). Overall, 81.1% demonstrated local invasion, excluding rupture of Bruch's membrane. Scleral invasion was present in 55.7% of eyes, and extrascleral extension was present in 8.2%. Mitotic activity was significantly reduced in eyes that had received preenucleation radiation treatment (P < .001). The number of macrophages in the tumor increased with increased pigmentation (P < .001) and increased necrosis (P < .01). The accuracy of diagnosis in the COMS is high, with histopathologic confirmation of the diagnosis at 99.7%. Extensive local invasion of the tumor was seen. Preenucleation irradiation significantly reduced the number of mitotic figures. An association was found regarding the presence of macrophages, the level of pigmentation, and degree of necrosis.