BACKGROUND: Because of their aggressive nature and limited treatment options, soft tissue sarcomas present a significant challenge for patients. Isolated limb perfusion with tumor necrosis factor α and melphalan (TM-ILP) has emerged as a promising modality against soft tissue sarcomas aimed at downstaging tumors with significant local invasion, offering a localized approach to deliver high doses of chemotherapy directly to the affected limb while minimizing systemic toxicity. However, its feasibility in centers with limited experience and its true impact on limb salvage remain unclear. Our study aims to address these knowledge gaps by evaluating outcomes in a diverse patient population and assessing factors that influence treatment success and limb preservation. QUESTIONS/PURPOSES: (1) What was the cumulative incidence of amputations at 12 months after TM-ILP in patients with tumors that were initially considered nonsalvageable? (2) What proportion of patients treated with this approach developed early severe complications, defined as death of the patient, compartment syndrome of the treated extremity, or a treatment reaction leading to limb amputation within 30 days from the ILP procedure? (3) What was the all-cause survivorship and survivorship free from local recurrence in patients treated with TM-ILP? METHODS: A retrospective observational study was conducted on patients who underwent TM-ILP for a soft tissue sarcoma that was deemed not amenable for limb salvage between July 2016 and June 2023. During this time, among a total of 528 patients treated for soft tissue sarcoma, 36 patients not considered candidates for a limb salvage procedure by a multidisciplinary tumor board were recommended for TM-ILP. The determination of limb nonsalvageability was based on the feasibility of achieving negative surgical margins and adequate soft tissue coverage after resection. Two patients declined TM-ILP, and a total of 34 patients were included in the study. After the TM-ILP treatment, an MRI was performed, and the feasibility of a limb salvage procedure was reassessed by the same multidisciplinary team against the same initial criteria. There were 12 females and 22 males, and the mean ± SD age was 55 ± 17 years. The most common sarcomas were of the lower extremity (62% [21 of 34]). The most frequent diagnoses were undifferentiated pleomorphic sarcoma (18% [6]) and myxoid liposarcoma (18% [6]). Seventy-six percent (26 of 34) of patients completed ILP followed by surgery, which took place between 2 and 3 months from TM-ILP. For the remaining eight patients, in four patients ILP could not be completed (two attributed to leaks, one attributed to arterial blockage, and one attributed to insufficient venous return), and the additional four patients elected not to proceed with surgery because of systemic disease progression. Seventy-nine percent (27 of 34) of patients were alive and had a documented follow-up of at least 1 year after treatment. To estimate the cumulative incidence of amputation-free survival, we used the survival package in R, version 4.3.2, considering death of the patient as a competing event. For Question 2, the proportion of patients experiencing severe complications was calculated by dividing the number of patients with at least one severe complication by the total number of patients in the cohort, expressed as a percentage. All-cause survivorship and survivorship free from local recurrence analysis for Question 3 was performed using a Kaplan-Meier estimator analysis with SPSS Statistics 29.0.2.0 (IBM). RESULTS: The cumulative incidence of amputations at 12 months after TM-ILP treatment was 13% (95% confidence interval [CI] 75% to 100%) in patients initially deemed to have unresectable lesions. Zero percent (0 of 34) had major complications, death attributed to TM-ILP treatment (0 of 34), compartment syndrome (0 of 34), and amputation attributed to reaction to TM-ILP (0 of 34). All-cause survivorship was 77% (95% CI 63% to 90%) at 12 months and 58% (95% CI 42% to 75%) at 24 months. Local recurrence-free survival at 12 months was 93% (95% CI 83% to 100%) and 84% (95% CI 71% to 97%) at 24 months. CONCLUSION: In this small, retrospective series, TM-ILP allowed limb-sparing surgery in patients with locally advanced or recurrent extremity sarcomas considered borderline resectable. While early results are encouraging, further studies with larger cohorts and longer follow-up times are needed to clarify the role of TM-ILP in multidisciplinary sarcoma care. LEVEL OF EVIDENCE: Level IV, therapeutic study.