For the treatment of choroidal melanoma, palladium-103 (103Pd) and ruthenium-106 (106Ru) plaque brachytherapy shows reduced toxicity compared with the historical standard iodine-125. No report has directly compared the clinical outcomes between 103Pd and 106Ru, and the reasons for the selection of one over the other remain purely theoretical. Patients with choroidal melanoma with apical tumor height up to 5 mm were included. Patients from Emory University were treated with 103Pd between 1993 and 2012. Patients from Cleveland Clinic were treated with 106Ru between 2005 and 2010. Medical records were retrospectively reviewed. We compared post-treatment visual acuity (VA), toxicity, and oncologic outcomes. 103Pd patients (n=124) and 106Ru patients (n=42) had a median follow-up of 4.2 and 5.0 years, respectively. Radiation retinopathy-free survival was similar for both radioisotopes, but 106Ru had lower grades of retinopathy (P=0.006). 103Pd was associated with worse VA preservation (≥20/40) by year 3 (odds ratio: 3.8; 95% confidence interval: 1.01–14.31, P=0.048). 103Pd was associated with higher distant metastases-free survival (DMFS) in multivariate analysis (hazard ratio: 0.10; 95% confidence interval: 0.02–0.38; P<0.001). 106Ru had lower grades of radiation retinopathy and improved long-term VA preservation, but also inferior DMFS, compared with 103Pd. Because of the inherent limitations of a retrospective analysis, the significance of the inferior DMFS for 106Ru remains unclear, although the suggestion of a slight inferiority in terms of DMFS for 106Ru is consistent with the other limited literature. On the basis of this study, we believe that both radioisotopes remain appropriate for the treatment of small choroidal melanomas up to 5 mm in apical height.