In cases where wide margins are not readily achievable during limb-sparing surgery (LSS) for soft tissue sarcoma (STS) of the extremity, intraoperative radiation therapy (IORT) may be used either alone or in conjunction with post-operative radiation (PORT) to improve local control with potentially decreased toxicities. The aim of this study is to describe wound healing issues following IORT for extremity STS.Retrospective analysis was performed for 92 patients treated with LSS and IORT for definitive management of extremity STS between 2012 and 2020 at a single institution. No patients received pre-operative RT. Major wound complications were classified as follows: secondary operation for wound repair requiring general/regional anesthesia, other invasive procedure for wound management, readmission for wound care, or persistent deep packing over 120 days. Univariate and multivariate binary logistic regression analyses were performed to identify factors associated with development of major wound complications.Median age at IORT was 58 years (IQR 35-71). Tumor distribution was 25% upper extremity and 75% lower extremity. The most common histologies were undifferentiated pleomorphic sarcoma (27%), synovial sarcoma (24%), and liposarcoma (18%). Tumors were grade 1 (14%), grade 2 (34%), and grade 3 (52%). 37% had received pre-operative chemotherapy. Median tumor size at resection was 7 cm (IQR 5-11), and 28% of patients had tumors over 10 cm in maximum dimension. The majority of patients received a prescribed IORT dose of 12 Gy (27%) or 15 Gy (66%). 30% of patients underwent complex surgical closure, as defined by use of a muscle flap (11%, n = 10), fasciocutaneous flap (5%, n = 5), and/or skin graft (16%, n = 15). 90% of patients were discharged in less than 1 week from LSS with IORT. 72% subsequently received PORT at a median time of 7 weeks from LSS (IQR 5-11). Overall, the rate of major wound complications was 18% (n = 17), of which 4 events occurred prior to PORT and 9 events occurred within 4 months from IORT. In total, 10% (n = 9) required a secondary operation for wound repair, 5% (n = 5) required an invasive procedure (commonly drainage of a seroma/hematoma), and 3% (n = 3) required readmission for wound care. None required persistent deep packing. On univariate analysis, factors predicting for development of a major wound complication included current smoking status (HR 15.86, P = 0.02) and complex wound closure (HR 3.32, P = 0.03), both of which remained significant on multivariate analysis. Factors that were not associated with wound complications included age, tumor size, IORT dose, pre-operative chemotherapy, and PORT.Despite the bias of selective use of IORT for more challenging surgical cases, IORT was not associated with increased rates of wound complications as compared to historical reports, and patients were able to transition to the next phase of therapy in a timely manner as part of optimal interdisciplinary management of STS.