Isolated limb perfusion with high-dose chemotherapy is an accepted treatment modality to achieve locoregional control in advanced melanoma of the extremities. The drug of choice is melphalan. Tumor necrosis factor-alpha is frequently added to melphalan in bulky disease, and this combination may be an option for repeat perfusion for recurrent melanoma after a first perfusion. Results of perfusions performed with tissue temperatures between 37 degrees C and 38 degrees C seem to be equivalent to those of the perfusions performed under mild hyperthermic conditions. Perfusion cannot be recommended as an adjunct to wide local excision in patients who have primary melanoma. Adjuvant perfusion in repeatedly recurrent limb melanoma, however, may be of value because it lengthens the limb recurrence-free interval and decreases the number of lesions per recurrence significantly. Regional toxicity of perfusion should be mild when risk factors are taken into account.