Background: The ISG-STS 1001 was an international, randomized, phase III, clinical trial for localized, high-risk, soft tissue sarcoma comparing neoadjuvant chemotherapy (ChT) with a standard regimen of epirubicin plus ifosfamide (EI) versus an histology-tailored regimen (HT) in five histologic types, within the context of an integrated multimodality strategy. In addition, in this study, a parallel group of patients (pts) was not randomized but just registered and treated with EI. Radiation-therapy (RT) could be delivered either pre-operatively (concurrent to ChT) or post-operatively, according to clinical judgement. Final results of ISG-STS 1001, published in 2020, showed a benefit in favor of EI, in terms of overall survival, in comparison to HT. Herein, we analyzed tolerability and activity of ChT with EI either in the standard arm of the trial or in the parallel group, whether alone and concurrent to RT. Methods: The EI regimen was made up of epirubicin 120 mg/m² plus ifosfamide 9 g/m². RT was delivered at a dose of 44-50 Gy pre-operatively or 60-66 Gy post-operatively. In the current analysis, toxicities related to EI were analyzed separately in the group receiving concurrent pre-operative ChT and RT and in the group treated with pre-operative ChT alone and receiving RT post-operatively. Surgical complications and radiological response according to RECIST were analyzed in the above mentioned two groups. Data on ChT dose-intensity will be provided. Results: Among the 548 pts (287 randomized and 261 registered) included in the ISG-STS 1001, 289 pts were considered for the current analyses (111 pts randomized in the EI arm and 178 pts just registered). 146 pts were treated with pre-operative RT and 143 with post-operative RT. In regard to toxicities, no statistically significant differences were found between pts treated with pre-operative concurrent ChT and RT and pts treated with pre-operative ChT alone. When surgical post-operative complications were considered, a higher number of wound dehiscence (9% vs 3.5%, respectively, p = 0.053) and seroma (10.5% vs 3%, respectively, p = 0.009) were observed in pts treated with pre-operative concurrent ChT and RT compared to pts treated with pre-operative ChT alone. Finally, a statistically significant association between RECIST response and pre-operative RT was found (p = 0.041), RECIST partial responses (PR) being 19% and 10% in pts receiving concurrent pre-operative ChT plus RT and in pts treated with pre-operative ChT alone, respectively. Conclusions: The concurrent administration of EI and RT was confirmed to be feasible and safe, resulting in an increased number of PR. Also given the final results of this randomized trial, favoring the EI arm, this combination may help when tumors are of borderline resectability or function preservation is a goal.