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Objective: Platinum resistance, defined as the lack of response or relapse within six months of platinum-based chemotherapy, is an important determinant of survival in gynecologic cancer. We used quantitative Mass Spectrometry to identify metabolic signatures that predict platinum resistance in patients receiving chemotherapy for gynecologic cancers., Methods: In this study 47 patients with adenocarcinoma of the ovary or uterus who were candidates for carboplatin plus paclitaxel submitted blood for quantitation of metabolites and surgical specimens for the isolation 3-dimensional organoids used to measure individual patient platinum resistance, ex vivo. Results were correlated with response, time to progression and survival., Results: Of 47 patients, 27 (64.3%) achieved complete remission with a mean time to progression of 1.9 years (± 1.5), disease-free survival of 1.7 years (± 1.4) and overall survival of 2.6 years (± 1.6) and a mean cisplatin lethal concentration 50% (LC50) = 1.15 μg/ml (range 0.4-3.1). Cisplatin LC50's correlated with a non-significant decrease in complete remission (RR [95% CI] =0.76 [0.46-1.27]), diminished disease-free survival (median: 1.15 vs. 2.99 years, p = 0.038) and with biochemical signatures of 186 metabolites. Receiver operating curves (ROC) of lipid ratios, branched chain amino acids and the tryptophan to kynurenine ratio identified patients at the highest risk of relapse and death (AUC = 0.933) with a sensitivity of 92.0% and specificity of 86.0% (p < 0.001)., Conclusions: Metabolic signatures in gynecologic cancer identify patients at the highest risk of relapse and death offering new diagnostic and prognostic tools for management of the advanced gynecologic tumors., Competing Interests: Declaration of Competing Interest Krishnansu S. Tewari, Robert E. Bristow, Fabio Cappuccini, Marcia B. Salzgeber, Anton M. Palma, Dirce M. L. Marchioni, Antonio A.F. Carioca, Kristine R. Penner, Jill Alldredge and Teresa Longoria have no conflicts of interest to declare. Paulo D'Amora (research grants from funding agencies: São Paulo Research Foundation (FAPESP); financial support for attending symposia and for educational programs: Nagourney Cancer Institute, American Association for Cancer Research, Rivkin Center; consultation: Metabolomycs, Inc.; intellectual property rights: Metabolomycs, Inc.; stockholder: Metabolomycs, Inc.). Steven S. Evans (employment: Nagourney Cancer Institute; stockholder: Metabolomycs, Inc.). Paula J. Addis-Bernard (employment: Nagourney Cancer Institute). Ismael Dale C.G. Silva (board director: Metabolomycs, Inc.; stockholder: Metabolomycs, Inc.). Robert A. Nagourney (board director: Nagourney Cancer Institute and Metabolomycs, Inc.; stockholder: Metabolomycs, Inc.). We certify that the submission is original work and is not under review at any other publication., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)