Objectives: To describe the postoperative course of patients who underwent hyperthermic isolated limb perfusion with recombinant tumor necrosis factor (TNF)-α and melphalan after pretreatment with recombinant interferon-γ as treatment for recurrent melanoma, primary nonresectable soft-tissue tumors, planocellular carcinoma, or metastatic carcinoma. To measure systemic TNF-α concentrations and relate these values with indices of disease severity. Setting: A 12-bed surgical intensive care unit (ICU) in a university referral hospital. Design: Prospective, descriptive study. Patients: Consecutive patients (n = 25) treated with hyperthermic isolated limb perfusion. Interventions: Blood samples were taken at regular intervals to determine TNF-α concentrations during and after hyperthermic isolated limb perfusion with recombinant TNF-α. Hemodynamic variables were obtained with a Swan-Ganz pulmonary artery catheter. Measurements and Main Results: All patients developed features of sepsis syndrome and required intensive care treatment. Most patients recovered quickly, with a median ICU stay of 2 days (range 1 to 25). Maximum systemic TNF-α concentrations ranged from 2284 to 83,000 ng/L (median 25,409) and returned to baseline values within 8 hrs. Despite these high concentrations of TNF-α, no patient died in the ICU, although the patient with the highest TNF-α concentration developed multiple organ failure and required continuous venovenous hemofiltration for 16 days. Linear regression analysis showed positive correlations between maximum TNF-α concentrations and systemic vascular resistance (p < .01), cardiac index (p < .02), Lung Injury Score (p < .02), prothrombin time (p < .02), and activated partial thromboplastin time (p < .05). Conclusions: Hyperthermic isolated limb perfusion with recombinant TNF-α leads to high systemic concentrations of TNF-α, probably due to leakage of recombinant TNF-α from the perfusion circuit, mainly through collateral blood flow. A sepsis-like syndrome is seen in all patients. Despite high concentrations of systemic TNF-α, this sepsis syndrome is short-lived and recovery is rapid and complete in most patients.