Isolated perfusion of the limbs (ILP) allows the delivery of high dose rTNF alpha in a closed system with acceptable side-effects. A protocol with a triple-drug regimen was based on the reported synergism of rTNF alpha with chemotherapy, with interferon-gamma, and with hyperthermia. In melanoma-in-transit metastases (stage IIIA or AB) we obtained a 91% complete response compared with 52% after ILP with melphalan alone. Leakage and release of nanograms levels of TNF alpha in the systemic circulation can be abrogated in most patients by low pump flow, continuous leak monitoring, extensive washout, and limb massage. In case of unavoidable leakage, appropriate intensive care results in minimal toxicity. The ILP with rTNF alpha appears to be a useful model for studying the biochemotherapy of cancer in humans.