Background: The Complexity INdex in SARComas (CINSARC) is a gene expression signature related to mitosis and chromosome integrity that stratifies risk for recurrence of soft tissue sarcoma (STS) patients. The aim of this study was to validate the prognostic value of CINSARC in patients enrolled in a randomised trial that compared histotype-tailored neoadjuvant chemotherapy with standard chemotherapy in patients with high-risk STS (ISG-STS 1001). Methods: CINSARC is 67-gene-expression-based signature that has been previously tested in retrospective series. The ISG-STS 1001 was a phase 3 RCT comparing histotype-tailored and anthracycline-based chemotherapy in localised, high-risk STS of the extremities or trunk wall, with one of five histological STS subtypes: high-grade myxoid liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumour, and undifferentiated pleomorphic sarcoma. Outcome variables were disease-free survival (DFS), overall survival (OS) and tumour response according to RECIST v1.1. Results: CINSARC was assessed in pre-treatment biopsies of 87 in 435 patients participating in the study. Thirty and 57 patients segregated in the lower (C1) and higher (C2) CINSARC risk group, respectively. Incidence of local recurrences (LR) and distant metastasis (DM) did not differ between C1 and C2 CINSARC groups [2 (6.6%) and 11 (19.3%) patients had a LR, respectively, and 10 (33.3%) and 14 (24.5%) patients had DM, respectively, P = 0.800]. Consistently, we did not observe statistically significant differences for DFS and OS between patients in the CINSARC C1 and C2 groups (log-rank test, P = 0.522 and P = 0.480, respectively). RECIST tumour response was analysed in a subset of patients (N = 39), showing that a RECIST SD was more likely in C1 (N = 12/14, 85.6%) compared to C2 (N = 18/25, 72%) group, while both RECIST PD and PR were more commonly detected in C2 [3/25 (12%) and 4/25 (16%), respectively] compared to C1 [0/14 (0%) and 1/14 (7.1%), respectively] group. Conclusions: In high-risk STS patients treated with preoperative chemotherapy within a RCT, CINSARC did not correlate with different DFS and OS. While this may well be due to a failure of this gene signature in this patient population, an alternative hypothesis is that preoperative chemotherapy may improve the prognosis of higher-risk patients. Clinical trial information: NCT01710176.