Background: Liver metastases from uveal melanoma carry a very poor prognosis. Hepatic artery infusions with yttrium(90) resin microspheres have some activity in this disease, and radiation and immunotherapy may be synergistic. The primary objective of this study was to determine the safety and tolerability of sequential yttrium(90) resin microspheres and immunotherapy with ipilimumab and nivolumab in metastatic uveal melanoma.Materials and Methods: Twenty-six patients with uveal melanoma with hepatic metastases were entered into a pilot study. Treatment consisted of two infusions of yttrium(90) resin microspheres, one to each lobe of the liver, followed in 2-4 weeks by immunotherapy with ipilimumab and nivolumab every 3 weeks for four doses, then maintenance immunotherapy with nivolumab alone.Results: Initial dosing of both yttrium(90) and immunotherapy resulted in excessive toxicity. With decreasing the dosage of yttrium(90) to limit the normal liver dose to 35Gy and lowering the ipilimumab dose to 1 mg/kg, the toxicity was tolerable, with no apparent change in efficacy. There was one complete and four confirmed partial responses, for an objective response rate of 20% and a disease control rate of 68%. The median progression-free survival was 5.5 months (95% confidence interval [CI]: 1.3-9.7 months), with a median overall survival of 15 months (95% CI: 9.7-20.1 months).Conclusions: With dose reductions, sequential therapy with yttrium(90) and immunotherapy with ipilimumab and nivolumab is safe and tolerable, and has activity in metastatic uveal melanoma. These results justify a controlled trial to demonstrate whether yttrium(90) resin microspheres add to the utility of combination immunotherapy in this disease.Clinical Trial Registration number: NCT02913417.