Objective: To evaluate late (more than 5 years) radiation failures after uveal melanoma treatment. Design: Comparison of three retrospective, interventional, partially randomized case series. Participants: Nine hundred ninety-six patients who were treated in several phase I, II, and III trials of uveal melanoma radiation. Main Outcome Measures: Follow-up period, treatment history, recurrence rates, type of recurrence, and mortality associated with late local recurrences. Results: Eleven of 996 irradiated uveal melanoma patients experienced intraocular recurrence more than 5 years after radiation. All 11 of these patients were treated with iodine 125 (I-125) brachytherapy. Late recurrences were detected between 5.5 to 15.3 years after treatment. These patients did not have either high-risk clinical parameters (thin, posterior tumors in proximity to the optic nerve) or radiation dosimetry characteristics (low dose-delivery radiation) associated with a known increased risk for tumor recurrence after radioactive plaques. The annualized incidence rate for regrowth was 1.9% per year between 5 and 15 years after I-125 brachytherapy. In contrast to charged particles, the risk of late recurrence after I-125 brachytherapy continued with increased follow-up. Conclusions: There was a significantly higher late recurrence rate with I-125 brachytherapy as compared with charged particle radiation. Although tumor enlargement 5 or more years after radiation can be the result of intratumor hemorrhage, in a patient treated with radioactive plaque, a late failure is a distinct possibility. (C) 2002 by the American Academy of Ophthalmology.