Survival of patients with uveal melanoma metastatic to the liver correlates strongly with disease control in the liver. Unfortunately, there are no standardized treatments for this chemoresistant disease. Selective internal radiation therapy (SIRT) has been tested as salvage therapy, but no data exist about its use as first-line therapy. The purpose of this study was to investigate the safety and efficacy of SIRT as first-line therapy in patients with uveal melanoma metastatic to the liver. Methods: This retrospective analysis of a prospectively collected cohort included 22 patients treated with first-line SIRT. Biochemical and clinical toxicities were recorded. Tumor response was determined according to the European Association for the Study of Liver Disease (EASL) criteria. Predictive factors of survival were analyzed by univariate and multivariate analysis. Overall survival was calculated using the Kaplan-Meier method with the log-rank test. Results: Grade 3-4 biologic and clinical toxicities occurred in 24% of patients (for both). According to the EASL criteria, disease control at 6 mo after SIRT was achieved in 15 (52%) of the 29 SIRT patients and was predictive of survival. Median overall survival from the first SIRT was 18 mo (95% confidence interval [95%CI], 8-28 mo). At the time of the analysis, 5 patients (23%) were still alive. In multivariate analysis, largest lesion size (hazard ratio [HR], 1.22; 95%CI, 0.98-1.53], liver tumor volume (HR, 1.002; 95%CI, 1.0004-1.003), subsequent systemic therapy (HR, 0.04; 95%CI, 0.006-0.24), and liver-directed locoregional therapy (HR, 0.204; 95%CI, 0.04-0.94) were predictive of survival. Conclusion: First-line SIRT is safe and produced promising outcomes in patients with uveal melanoma metastatic to the liver. Subsequent systemic and liver-directed locoregional therapies ameliorated survival, highlighting the potential for improved outcomes with combination approaches. The results of this study suggest that prospective trials using first-line SIRT should be considered.