To describe the first clinical experience with palladium-103 (103Pd) ophthalmic plaque radiotherapy for choroidal melanoma. Phase-I (nonrandomized) clinical trial. Eighty patients with uveal melanomas were diagnosed by clinical examination, found to be negative for metastatic disease, and offered 103Pd radioactive plaque treatment. Nine patients were concurrently treated with microwave hyperthermia. Palladium-103 ophthalmic plaque radiotherapy was employed for each patient. Eye plaques were sewn to the episclera to cover the base of the intraocular tumor, radiation was continuously delivered over 5 to 7 days, and then the plaques were removed. A mean apical dose of 81 Gy was delivered. The authors evaluated the ease of use of 103Pd seeds within standard gold eye plaques. Patient-related outcomes were control of tumor growth, change in visual acuity, the development of radiation damage (retinopathy, optic neuropathy, and cataract), and metastatic disease. From September 1990 to December 1997, 80 patients were treated with 103Pd and followed for an average of 38 months. Two patients were lost to follow-up. During this time, the authors found that 103Pd seeds were equivalent to iodine-125 (125I) with respect to plaque manufacture and ease of dosimetric calculations. Two patients in this series were treated for tumor recurrence after 125I plaque radiotherapy. They both failed secondary 103Pd treatment and were enucleated. When 103Pd was used as a primary treatment, it controlled the growth of 75 of 78 tumors (96%). Overall, there have been six enucleations: three failures of primary treatment, two failures of retreatment, and one for neovascular glaucoma. Visual acuity evaluations at the 36-month follow-up visit (including the enucleated patients) revealed that 38% of eyes had decreased 3 or more lines of vision, and 77% were 20/200 or better. Palladium-103 plaque radiotherapy can be used to treat uveal melanomas. Compared with 125I, computerized dosimetry suggests a more favorable dose distribution with 103Pd. Treatment of most patients resulted in tumor shrinkage and preservation of functional vision. The authors have noted no complications that might preclude the use of 103Pd ophthalmic plaque radiotherapy for choroidal melanoma.