Objective: To date, there are no predictive biomarkers to guide selection of patients with gastric cancer (GC) who benefit from paclitaxel. Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) was a 2×2 factorial randomised phase III study in which patients with GC were randomised to Pac-S-1 (paclitaxel +S-1), Pac-UFT (paclitaxel +UFT), S-1 alone or UFT alone after curative surgery., Design: The primary objective of this study was to identify a gene signature that predicts survival benefit from paclitaxel chemotherapy in GC patients. SAMIT GC samples were profiled using a customised 476 gene NanoString panel. A random forest machine-learning model was applied on the NanoString profiles to develop a gene signature. An independent cohort of metastatic patients with GC treated with paclitaxel and ramucirumab (Pac-Ram) served as an external validation cohort., Results: From the SAMIT trial 499 samples were analysed in this study. From the Pac-S-1 training cohort, the random forest model generated a 19-gene signature assigning patients to two groups: Pac-Sensitive and Pac-Resistant. In the Pac-UFT validation cohort, Pac-Sensitive patients exhibited a significant improvement in disease free survival (DFS): 3-year DFS 66% vs 40% (HR 0.44, p=0.0029). There was no survival difference between Pac-Sensitive and Pac-Resistant in the UFT or S-1 alone arms, test of interaction p<0.001. In the external Pac-Ram validation cohort, the signature predicted benefit for Pac-Sensitive (median PFS 147 days vs 112 days, HR 0.48, p=0.022)., Conclusion: Using machine-learning techniques on one of the largest GC trials (SAMIT), we identify a gene signature representing the first predictive biomarker for paclitaxel benefit., Trial Registration Number: UMIN Clinical Trials Registry: C000000082 (SAMIT); ClinicalTrials.gov identifier, 02628951 (South Korean trial)., Competing Interests: Competing interests: RS: Advisory board: BMS, Merck, Eisai, Bayer, Taiho; honoraria for talks: MSD, Eli Lilly, BMS, Roche, Taiho; Travel funding: Roche, Astra Zeneca, Taiho, Eisai; Research funding: Paxman Coolers, MSD. These are outside the submitted work.TO: Research Funding: Taiho pharmaceutical, Chugai pharmaceutical, Ono pharmaceutical, Daiitisankyo pharmaceutical, Nippon Kayaku and Eli Lilly Japan K. K. Lecture fees: Nippon Kayaku, Ono pharmaceutical and Bristol-Myers Squibb K. K. Speaker Bureau: Taiho pharmaceutical, Chugai pharmaceutical, Ono pharmaceutical, Bristol-Myers Squibb K. K and Eli Lilly Japan K. K. These are outside the submitted work. TY: Lecture fees from: MSD, ONO, BMS, Taiho, Chugai, Daiichi-Sankyo, Lilly, Johnson & Johnson, Covidien and Olympus. Personal grant from Lilly. These are outside the submitted work. KY: Personal fees from Taiho Pharm and Bristol-Myers Squibb, during the conduct of the study; grants and personal fees from Asahi Kasei Pharma, Chugai Pharm., Covidien Japan, Daiichi Sankyo, Eisai, Eli Lilly Japan, Johnson & Johnson, MerkSerono, MSD, Nippon Kayaku, Novartis, Ono Pharm., Otsuka Pharm., Sanofi, Tsumura, Yakult Honsha, Takeda Pharm., grants from Abbott, Abbvie, Astellas, Biogen Japan, Celgene, GlaxoSmithKline, KCI, Kyowa Kirin, Meiji Seika Pharma, Toray Medical, Koninklijke Philips, personal fees from AstraZeneka, Denka, EA Pharma, Olympus, Pfizer, Sanwa Kagaku Kenkyusho, SBI Pharma, Teijin Phamra, TERUMO. These are outside the submitted work. YR: Speaker Bureau from; Daiichi-Sankyo, Johnson & Johnson, Otsuka, Lilly, Taiho pharmaceutical, Bristol-Myers Squibb. Research Funding: Taiho pharmaceutical, Abbott, Asahi Kasei, Daiichi-Sankyo, Tsumura & Co., Covidien, Zeria pharmaceutical, Otsuka, EA Pharma, Johnson & Johnson. These are outside the submitted work. YM: Lecture fees from AstraZeneca, Taiho, Chugai, and Daiichi-Sankyo. Consigned research fund from Toso company, Japan. These are outside the submitted work. MM: Research Funding from Chugai pharmaceutical, Teijin pharmaceutical, Daiitisankyo pharmaceutical, Takeda pharmaceutical, Terumo, Japan Lifelin, Senkod. These are outside the submitted work. ST: Lecture fee: Bayer Yakuhin, Amgen Astellas BioPharma K.K. Consultation fee: Boehringer Ingelheim. These are outside the submitted work. ADJ: honoraria from AstraZeneca, Janssen and MSD, travel funding from Perkin Elmer, and research funding from Janssen. These are outside the submitted work. HG: honoraria for participation in an expert meeting from MSD. These are outside the submitted work. AL-KT: Lecture fees Chugai Pharmaceutical. These are outside the submitted work. PT: Travel: Illumina, Research funding: Thermo Fisher, Kyowa Hakko Kirin. These are outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)