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Background: This case report aims to describe an adverse reaction following intra-arterial melphalan chemotherapy in a 48-year-old female patient with choroidal melanoma. The chemotherapy was part of a phase I clinical trial (MELCOM Study - ClinicalTrials.gov ID: NCT05893654), designed to evaluate its efficacy as a bridge to Ru-106 brachytherapy for treating large uveal melanomas. This is the first reported case of a cutaneous reaction to melphalan in an adult patient. Observations: Upon administration of melphalan, the patient developed an erythematous periorbital skin lesion three days post-treatment. The lesion evolved into a hyperchromic brownish macule that later disappeared spontaneously. Conclusions and Importance: While melphalan successfully reduced the tumor dimensions, making the patient eligible for subsequent Ru-106 brachytherapy, it led to a cutaneous reaction previously reported only in pediatric patients. Despite this aesthetic complication, the therapy was effective in tumor reduction, highlighting the need for further studies to assess the risk-benefit profile of intra-arterial melphalan chemotherapy in adult populations.