In advanced melanoma of the limbs with in-transit metastasis, melphalan with isolated limb perfusion (M-ILP) produces around 50% complete remissions (CR). The combination of melphalan with tumour necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma) in isolated limb perfusion (TIM-ILP) gives around 80% CR. A prospective randomised phase II study compared 32 patients who received TIM-ILP with 32 patients who received TM-ILP (without IFNgamma). The overall remission rate (ORR) and the CR rate were superior with TIM-ILP as compared to TM-ILP, 100% vs. 91% and 78% vs. 69% respectively, but the differences are not significant. Given the efficacy of M-ILP on in-transit metastasis, the procedure was tested as an adjunct to surgery in high-risk (Breslow > or = 1.5 mm) primary melanoma of the limbs. Through the combined effort of the melanoma groups of the European Organization for Research and Treatment of Cancer (EORTC), the World Health Organization (WHO), and the North American Perfusion Group, 832 evaluable patients from 16 centres were entered in a phase III study. Median followup is 6.4 years. There was a trend for a longer disease-free interval after M-ILP. The difference is significant if the patients without elective lymph node dissection (ELND) are separately analysed, with a high significance in the 1.5 to 3 mm thickness subgroup. The occurrence of in-transit metastases was reduced from 6.6% to 3.3% by M-ILP. There was, however, no benefit of M-ILP in terms of survival. Prophylactic M-ILP cannot be recommended as a standard adjunct to surgery in high-risk primary limb melanoma. TIM-ILP or TM-ILP is a regional therapy with a very high regional response rate on melanoma in-transit metastasis.