Isolated limb infusion (ILI) is a minimally invasive technique of delivering regional chemotherapy in patients with advanced melanoma or soft-tissue sarcoma of the limb. We report the final results of the first clinical trial of ILI in North America (NCT00004250). Eligible patients had recurrent melanoma or unresectable soft-tissue sarcoma of the limb. Angiographic catheters were positioned just above the knee or elbow of the extremity. General anesthesia was performed, a proximal tourniquet inflated, and a normothermic, low flow, hypoxic infusion of melphalan and dactinomycin circulated through the involved limb for 20 min. Tumor response and morbidity were assessed using standard criteria. Thirty-seven patients were accrued to the trial and 44 ILIs were performed (eight patients had two ILIs); one patient was not treated. Of the 32 evaluable patients, 17 (53%) had a significant response at 3 months: 25% of patients had a complete response and 28% of patients had a partial response. The median duration of complete response was 1 year (5-32 months). Morbidity was acceptable, with peak erythema, edema, and pain experienced at 2 weeks and considered 'moderate' in most patients. No patients developed compartment syndrome or required amputation because of ILI. ILI is well tolerated. More than half of the treated patients experienced a complete or partial response.