A 75-year-old white man with a history of nonmelanoma skin cancer was first diagnosed as having a Clark level IV malignant melanoma (Breslow depth, 1.57 mm) of the left lower extremity approximately 19 months prior to presentation. The primary melanoma was treated with therapeutic excision with negative margins, and the patient deferred sentinel node evaluation. Multiple in-transit metastatic melanoma lesions limited to the left leg appeared several months later and were subsequently treated with standard isolated limb infusion (ILI) with melphalan and dactinomycin. Standard ILI delivers 10 to 20 times the typically tolerated systemic chemotherapy dose directly to the affected tourniquet-wrapped extremity through vascular cannulas.