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Simple Summary Percutaneous hepatic perfusion (PHP) with melphalan is an innovative technique that facilitates the delivery of high-dose chemotherapy to hepatic tumors while limiting systemic toxicity. Patients with uveal melanoma often initially develop hepatic metastases, which are responsive to melphalan; thus, they are particularly eligible candidates for PHP. Additionally, effective systemic therapies for metastatic uveal melanoma are still lacking; hence, further insight into liver-directed methods such as PHP is crucial. The aim of this retrospective two-center study was to pool the data of patients with liver-dominant metastatic uveal melanoma treated with PHP and analyze peri-interventional complications, response, and survival. Abstract Percutaneous hepatic perfusion (PHP) delivers high-dose melphalan to the liver while minimizing systemic toxicity via filtration of the venous hepatic blood. This two-center study aimed to examine the safety, response to therapy, and survival of patients with hepatic-dominant metastatic uveal melanoma (UM) treated with PHP. A total of 66 patients with liver-dominant metastasized uveal melanoma, treated with 145 PHP between April 2014 and May 2020, were retrospectively analyzed with regard to adverse events (AEs; CTCAE v5.0), response (overall response rate (ORR)), and disease control rate (DCR) according to RECIST1.1, as well as progression-free and overall survival (PFS and OS). With an ORR of 59% and a DCR of 93.4%, the response was encouraging. After initial PHP, median hepatic PFS was 12.4 (confidence interval (CI) 4–18.4) months and median OS was 18.4 (CI 7–24.6) months. Hematologic toxicity was the most frequent AE (grade 3 or 4 thrombocytopenia after 24.8% of the procedures); less frequent was grade 3 or 4 hepatic toxicity (increased aspartate transaminase (AST) and alanine transaminase (ALT) after 7.6% and 6.9% of the interventions, respectively). Cardiovascular events included four cases of ischemic stroke (2.8%) and one patient with central pulmonary embolism (0.7%). In conclusion, PHP is a safe and effective salvage treatment for liver-dominant metastatic uveal melanoma. Serious AEs—though rare—demand careful patient selection.