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Objective: To investigate the oncologic and functional outcomes of a large cohort of patients with a favorable stage of circumscribed and diffuse iris melanoma who underwent primary proton treatment and the risk factors related to initial tumor characteristics and the treatment field architecture., Design: Retrospective, single-center, case study., Participants: We reviewed 225 patients with iris melanoma who were consecutively treated with proton beam therapy at our institution between 1998 and 2020., Methods: We performed Kaplan-Meier time-to-event analyses and multivariate Cox proportional hazard analyses to identify the impacts of tumor characteristics and target volumes on oncologic and functional outcomes., Main Outcome Measures: We measured local tumor control, eye preservation rates, metastasis-free survival, cataract and glaucoma-directed surgery, intraocular pressure, and changes in visual acuity., Results: Of the 192 patients with tumors confined to the iris (T1a-c) who underwent proton therapy as primary treatment, a total of 166 patients (mean age, 58.4 years; 88 women) with a minimum follow-up of 6 months were included. Multifocal or diffuse tumor spread was present in 77 (46.4%) patients. The median follow-up time was 54.0 (interquartile range, 27.4-91.8 months) months. Local recurrence occurred in 2 patients (1.2%) with circumscribed iris melanoma. Enucleation was a rare event (n = 5, 3%) and no patient developed metastatic disease. A large-treatment field (full aperture, involving > 10 clock hours) was identified as a risk factor for the development of secondary glaucoma (hazard ratio [HR], 6.3; P < 0.001) and subsequent surgical interventions (HR, 10.85; P < 0.001). The large-treatment field group showed a significant decline in visual acuity (logarithm of the minimum angle of resolution > 0.3; log-rank P < 0.0001), which was associated with secondary glaucoma (HR, 3.40; P = 0.002)., Conclusions: Proton therapy provides an effective, noninvasive treatment option for patients with a favorable stage of iris melanoma. Irradiation of the anterior segment for up to 10 clock hours is associated with a low risk of the development of secondary glaucoma and vision loss., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)