Background: We investigated the prognostic relevance of % change in LTD in patients (pts) with localized high-risk STS treated with neoadjuvant chemotherapy in a phase 3 randomized trial (NCT01710176), aimed at comparing 3 cycles of a neoadjuvant histology-tailored (HT) over 3 cycles of standard anthracycline + ifosfamide chemotherapy (S). Methods: Pts with localized high-risk STS of extremities or trunk wall, and a diagnosis of myxoid liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumors, undifferentiated pleomorphic sarcoma were randomly assigned to receive 3 cycles of S or HT. Pts affected by myxofibrosarcoma, pleomorphic liposarcoma, pleomorphic rhabomyosarcoma unclassified spindle cell sarcoma were prospectively registered and treated by S. Change of LTD was assessed comparing baseline dimension with that measured after 3 cycles of S or HT, before surgery. Only pts treated with neodjuvant chemotherapy alone were selected for the analysis. We first investigated Overall Survival (OS) from surgery of the groups identified by “any % reduction”, “no-change” or “increase” in LTD by Kaplan-Meier estimates and log-rank tests. Then we searched for cutoffs able to separate prognosis among pts with a LTD reduction applying the change-point method proposed by Contal - O’Quigley. Results: Of 325 pts who entered the study and evaluable for response, 181 received neoadjuvant chemotherapy alone (92 S and 89 HT group respectively) and were analyzed, while 144 received concurrent chemo-radiotherapy and were excluded. In the whole population, % changes in LTD were significantly associated (log rank p = 0.032) to OS. “Any % reduction in LTD (101/181pts) displayed a better prognosis compared to “no-change” (28/181 pts) or “any % increase” (52/181). The change-point analysis was applied to all, S and HT groups separately; a cutoff of = / > 18.75% decrease in LTD was the optimal predictor of outcome for the S group (p = 0.031), while no size cut-off could be identified for the HT group. Conclusions: In our study, % change in LTD of pts treated with neoadjuvant chemotherapy for localized high-risk STS correlated with OS. However, a % decrease in LTD cut-off able to predict the best outcome could be identified only for pts treated in the S group, while no differences in outcome were found by any % LTD change in the HT group. Interestingly, the LTD cut-off identified in the S group was lower than the one selected to define a response by RECIST ( = / > 18.75% decrease in LTD vs = / > 30%). Clinical trial information: NCT01710176.