Background: We report our long term results of isolated limb infusion (ILI) in cases of locally advanced softtissue sarcoma (ASTS) of the extremities. Methods: Forty cases of ASTS received ILI with doxorubicin. Preoperative external beam radiotherapy started within 3-7 days after ILI was administered. After 3-7 weeks, surgery was performed aiming at limb preservation. The long term outcome of these cases (Group I) was reported and compared to the outcome of comparable group of patients followed prospectively and treated by neoadjuvant systemic chemotherapy (NACT) and external irradiation (Group II). Results: The study included 40 cases in Group I, and 46 cases in Group II. Overall response to preoperative treatment was 85% in Group I versus 43% in Group II. Wide local excision was performed for 75% of Group I patients and in 34% of Group II cases. After a median follow up period of 76 months, local recurrence rate was 35% in Group I and 67% in Group II (P= 0.02). The overall survival rate was 60% in Group I and 35% in Group II (p= 0.008). Only initial response to ILI was associated with overall survival in Group I. Conclusion: The outcome of ILI in management of ASTS is significantly better than systemic NACT in terms of disease free and overall survival.