Isolated limb perfusion (ILP) with melphalan is an effective treatment for recurrent melanoma, but complete remission is achieved only in about 40% of patients. Regional toxicity is common, causing short-term disability and occasional longterm incapacity. Methods to maximize the efficacy and minimize the toxicity were investigated in 210 ILPs undertaken at the Sydney Melanoma Unit. Toxicity was found to be related to peak melphalan concentration, as well as to the area under the curve and maximum temperature. A dye dilution technique has been developed to measure perfusion circuit volume, so that a drug dose can be given to achieve an appropriate concentration. ILP with cisplatin was less effective and produced greater toxicity than ILP with melphalan; other drugs and drug combinations warrant investigation. Prophylactic ondansetron successfully controlled post-operative nausea and vomiting in most patients. Daily measurement of serum creatine phosphokinase (CPK) allowed early recognition of impending severe toxicity, with the greatest risk if CPK exceeded 1000 IU/l after the first post-perfusion day. Isolated limb 'infusion' (ILI) with melphalan, using percutaneously inserted catheters, is a much simpler procedure than ILP and has been found to be effective and easily repeated. The morbidity of ILP and ILI may be minimized by excluding the foot or hand with a rubber bandage.