Isolated limb perfusion (ILP) is a surgical technique that enables the administration of high-dose chemotherapy while minimizing serious systemic side effects. The clinical value and indications are well established for skin and soft tissue tumors on limbs. For skin tumors, this technique is mainly indicated for melanoma with in-transit metastasis. For soft tissue tumors--sarcoma and osteosarcoma--it is useful as a palliative technique to reduce the tumoral mass. Limb perfusion can also be an option in other tumors, such as advanced stage squamous cell carcinoma or Merkel cell carcinoma. We present a case report of a 68-year-old man with Merkel cell carcinoma on the right tibiotarsical region, with in-transit metastasis throughout the whole lower limb. Regional chemotherapy involving ILP with melphalan and tumor necrosis factor-alpha (TNFalpha) was performed in order to avoid amputation; the primary tumor was not excised. A steady regression of the disease was observed, with complete resolution of all visible in-transit metastases at the 45th day post-perfusion. However, systemic metastasis leading to fatal outcome occurred 4 months later. Although there was no change in the patient's prognosis, ILP was able to avoid limb amputation as it controlled local-regional disease and produced complete regional remission. The addition of TNFalpha to melphalan in ILP appears to produce greater efficacy in the treatment of patients with bulky tumors or a large number of in-transit metastases.