Background: Uveal melanoma is the most common primary intraocular malignancy in adults. Despite successful control of the primary tumor, metastatic disease will ultimately develop in approximately 50% of the patients, with the liver being the most common site. The median survival for patients with liver metastases is about 6-12 months, and there are only few systemic treatment options available that moderately prolong survival. A previous trial using isolated hepatic perfusion (IHP) has suggested a 14-month increase in overall survival, compared with a historical control group consisting of the longest surviving patients in Sweden during the same time period (26 vs. 12 months). Methods: In this multicenter randomized, controlled, phase III trial, patients with previously untreated isolated liver metastasis from uveal melanoma were randomized between 2013 and 2021 to receive IHP or best alternative care (control group). The primary end point is overall survival at 24 months, but here we report the secondary outcomes of response according to RECIST 1.1 criteria, progression-free survival (PFS), hepatic PFS (hPFS) and toxicity. Results: A total of 93 patients were randomized, with three patients in each group being excluded due to either withdrawal of consent or inappropriate enrollment, and a total of 87 patients were assigned to either IHP group (43 patients) or control group (44 patients). In the IHP group, 41 (89%) patients were treated per protocol, and in the control group, 49% of the patients were treated with chemotherapy, 39% with immunotherapy and 9% with localized treatment interventions. In an intention-to-treat analysis, the overall response rate (ORR) in the IHP group was 40% (17/43) compared to 4.5% (2/44) in the control group (p<0.0001). The median hPFS in the IHP group was 9.1 months (95% CI, 5.6 to 13.4 months), compared to 3.3 months (95% CI, 2.9 to 4.0 months) in the control group (p<0.0001). The median PFS in the IHP group was 7.4 months (95% CI, 5.2 to 11.6 months), compared to 3.3 months (95% CI, 2.9 to 3.7 months) in the control group (p<0.0001). There were 14 treatment-related serious adverse events in the IHP group, where vascular complication and infections were the most common side effects, compared to 13 in the control group where immunotherapy related side effects were most common. There was one treatment related death in the IHP group. Conclusions: Treatment with IHP resulted in superior ORR, hPFS and PFS compared to best alternative care among previously untreated patients with isolated uveal melanoma liver metastasis. Clinical trial information: NCT01785316.