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Background Uveal melanoma is a rare melanoma subtype characterized by a liver-dominant pattern of metastasis which is associated with a lack of durable responses to immunotherapies. Adoptive cell transfer of autologous tumor-infiltrating lymphocytes (TILs) has been shown to induce responses in a subset of patients with metastatic uveal melanoma. The safety and feasibility of locoregional administration of TIL therapy via hepatic arterial infusion (HAI) have not previously been evaluated.Patients and methods This prospective, open-label, phase I trial investigated the safety and feasibility of one-time TIL therapy administered via HAI in patients with liver metastases of uveal melanoma. Preconditioning chemotherapy with melphalan (1 mg/kg, intravenous) was administered on day −5. TILs were delivered via percutaneous catheterization of the hepatic artery according to a dose escalation scheme (0.1, 0.3, or 1×10 9 cells) on day 0. Patients received daily subcutaneous interleukin-2 (IL-2, 2 MIU) up to 14 days after TIL administration. The primary endpoint was the incidence and severity of adverse events (AEs). Secondary endpoints included clinical efficacy and the feasibility of TIL production using a semiautomated manufacturing system.Results Six patients received TIL therapy manufactured using the CliniMACS Prodigy platform; five were treated according to protocol, while one received a lower TIL dose than planned. All had received prior systemic treatment. No AEs related to the HAI procedure were observed. All patients experienced grade ≥3 hematologic AEs related to preconditioning chemotherapy, and two patients experienced grade ≥3 AEs attributed to TIL/IL-2. Best overall response was stable disease in all patients (100%). Median progression-free survival was 4 months, and median overall survival was 14 months.Conclusions TILs can be manufactured using the CliniMACS Prodigy. Administration of TIL via HAI was safe and feasible in patients with liver-dominant metastatic uveal melanoma. The used regimen appears insufficient to achieve durable clinical efficacy and implies a need for further testing to obtain conclusive results.Trial registration numbers NCT04812470, EUCT number: 2024-512877-28-00, EudraCT number: 2020-006126-31.