We report here the results of 27 patients who underwent hyperthermic isolated limb perfusion with low-dose TNFalpha (1 mg) and doxorubicin (8.5 mg/l of limb volume) for locally advanced soft tissue sarcomas. A tumor response was observed in 85% of cases. After a median follow-up of 30 months, limb salvage and local disease control were achieved in 82 and 85% of patients, respectively. Locoregional toxicity was low or mild in 14 patients, while 2 patients had severe limb toxicity. Systemic side effects were negligible. The perfusate/plasma area under the curve (AUC) ratio for TNFalpha was 56. HILP with low-dose TNFalpha and DXR proved to be an active neoadjuvant drug regimen against limb-threatening STS.