Histopathologic studies were performed on 38 eyes in patients with uveal melanoma who had enucleation. Of the 38 eyes examined, enucleation was required in 11 (29%) following episcleral radioactive plaque therapy (RPT), which was performed in 83 patients. The reasons for enucleation in the 11 patients who had RPT were progressive tumor in 5 and treatment complications in 6 eyes. The histologic findings in these 11 patients were compared to those seen in 7 patients (18%) who received a planned course of preoperative external beam radiotherapy (RT) prior to enucleation and with 20 uveal melanoma patients (53%) who were treated with enucleation alone. Tumor necrosis was found in the eyes of patients from all three groups examined. It was, however, seen more frequently and to a greater extent in the 11 RPT patients as compared to the 7 preoperative RT and 20 enucleation alone patients, p = .01. There was no difference in the incidence or extent of tumor necrosis in the 7 preoperative RT patients as compared to the 20 primary enucleation patients, p = .18. In all 3 study groups, no correlation was found between tumor size and necrosis. In the 11 RPT patients, necrosis was independent of cell type and the radiation dose. As expected, the RPT patients had a greater incidence of neovascularization on the iris and scleral necrosis than those of the other two study groups (70 vs. 12.5% and 33 vs 0%, respectively), p = .004. A major effort needs to be made to optimize episcleral RPT in order to reduce treatment complications and increase the incidence of primary tumor control.