Hyperthermic isolation limb perfusion is considered standard therapy in the treatment of patients with regional in-transit metastatic melanoma of the extremities. Its role in the adjuvant treatment of patients with melanoma metastatic to regional nodes is less well defined. This review describes patient subgroups at high risk for local-regional recurrence after regional lymphadenectomy and the role of adjuvant perfusion in preventing local-regional recurrence and prolonging survival in these patients. Logistic problems in attempting to prove that adjuvant limb perfusion is beneficial are discussed.