Abstract Background Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver. Methods Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6–8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety. Results Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6–69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively. Conclusions M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.