Purpose: To evaluate the outcomes of iris melanoma managed with plaque radiotherapy on the basis of the initial presence or absence of glaucoma. Design: Retrospective, comparative case series. Participants: A total of 144 patients. Intervention: Custom-designed iodine-125 plaque radiotherapy delivering planned 8000 cGy to melanoma apex using transcorneal application. Main Outcome Measures: Tumor control and treatment-related complications. Results: Of 144 patients with iris melanoma, glaucoma was present at the initial visit in 58 (40%). Causes of elevated intraocular pressure included angle infiltration by melanoma in 50 patients (86%), angle neovascularization in 4 patients (7%), and hyphema in 4 patients (7%). At presentation, the eyes displaying iris melanoma with glaucoma (vs. without glaucoma) were statistically more likely to display angle tumor (66% vs. 43%), with minimal thickness (1.9 vs. 2.9 mm), and melanoma seeding in iris stroma (7 vs. 3 clock hours) and angle (5 vs. 2 clock hours). Plaque radiotherapy was performed in all cases. Kaplan-Meier estimates at 7 years post-treatment revealed no statistical differences in outcomes of local recurrence (14% vs. 15%), enucleation (14% vs. 11%), or metastasis (2% vs. 0%) comparing eyes with and without glaucoma. Of the entire group, multivariate analysis for factors predictive of recurrence included partial (vs. complete) anterior segment irradiation and post-radiotherapy glaucoma. Factors related to enucleation included diabetes mellitus, poor initial visual acuity, higher radiation dose to tumor apex, and tumor recurrence. There were no factors predictive of metastasis. Conclusions: Iodine-125 plaque radiotherapy provides adequate tumor control for iris melanoma with a low metastatic potential of 1% at 7 years. Iris melanoma with secondary glaucoma showed a statistically significant greater likelihood of flat tumor with iris and angle seeding and no difference in outcomes compared with eyes without glaucoma.