Standard treatment for soft tissue sarcoma (STS) includes conventionally fractionated radiotherapy at 1.8-2 Gy/fx followed by surgical resection resulting in wound complication rates of 35% (O’Sullivan et al., Lancet 2002). STS has a low α/β ratio suggesting higher doses per fraction should lead to improved tumor control with a similar side effect profile. This single arm phase 2 clinical trial assessed the safety of preoperative hypofractionated radiotherapy in patients with STS. Patients with newly diagnosed and histologically confirmed Stage I-III STS of the extremity or chest wall were enrolled on this protocol at one institution. Patients were deemed resectable with negative margins and treated with radiotherapy to 3500 cGy in 5 fractions administered every other day prior to undergoing resection 4 to 6 weeks after completion of treatment. The primary outcome was wound complications assessed using the NCIC definition. Secondary outcomes included local control, disease free survival, and overall survival. Twenty-six patients enrolled with 24 completing surgical resection. Of these patients, 14 were male and 10 female and the median age was 66. Median tumor size was 9.5 cm. The vast majority of patients had undifferentiated histology (n=11, 46%) followed by liposarcoma/leiomyosarcoma (n=6, 25%), myxofibrosarcoma (n=5, 21%), and other (n=2, 8%). Tumor anatomic location was proximal lower extremity/buttock, upper extremity, distal lower extremity, and chest wall in 71%, 13%, 8%, and 8%, respectively. Most patients presented with stage III disease (79%) followed by I (13%) and II (8%). Histologic grade was high, low, and intermediate in 79%, 13%, and 8%, respectively. Two patients (8.3%) had positive margins on surgical specimens and plastic surgery was involved in 9 of the operations (38%). Median RT elapsed days was 9.5 and the median time from initiation of RT to time of surgery was 50.5 days. At a median follow-up time of 19.8 months, 6 patients (25%) experienced a post-operative wound complication. Local control was 100%. Five patients developed distant metastatic disease (20.8%) with a median time to distant metastases of 15.4 months. Two patients (8%) died of metastatic disease. Results of preoperative hypofractionated radiotherapy for treatment of patients with STS of the extremity and trunk demonstrates post-operative wound complication rates comparable to historical rates using conventionally fractionated RT. Although local control was optimal at 100%, further follow-up is needed to corroborate these findings.