Background: Although the classic form of Kaposi sarcoma is considered indolent and benign, at times its evolution is more severe, with an acute onset and debilitating complications necessitating aggressive treatment and even amputation. Objective: To evaluate the efficacy of hyperthermic isolated limb perfusion (ILP) with tumor necrosis factor α and melphalan as a limb- sparing modality for extensive regional Kaposi sarcoma. Setting: University hospital and national referral center. Patients: Five patients, aged 60 to 82 years, with extensive, symptomatic, classic Kaposi sarcoma of the lower limb were operated on. All were candidates for amputation owing to debilitating symptoms. Interventions: Patients underwent ILP through the iliac (n = 2), femoral (n = 2), and popliteal (n = 1) vessels. Tumor necrosis factor α, 4 mg, and melphalan, 1.5 mg/kg body weight, were perfused for an overall time of 90 minutes. The limb was heated to 40°C. Clinical and pathological responses were recorded for all patients after 6 to 8 weeks. Results: The overall response rate was 100%: 1 of 5 patients had complete response and 4 of 5 had partial response. Two patients had progression of disease 2 months after ILP but one of them was asymptomatic and did not require any further treatment. The second patient underwent amputation. Thus, limb preservation was achieved in 80% (4 of 5 patients). Median follow-up was 24 months. There were no deaths associated with treatment or major system complications. Local complications were all reversible. Conclusion: These findings suggest that hyperthermic ILP with tumor necrosis factor α and melphalan can be considered an effective palliative and limb-sparing treatment modality for extensive Kaposi sarcoma.