Rationale and Objectives: Immune checkpoint inhibitors (ICIs) have improved lung cancer prognosis; however, ICI-related interstitial lung disease (ILD) is fatal and difficult to predict. Herein, we hypothesized that pre-existing lung inflammation on radiological imaging can be a potential risk factor for ILD onset. Therefore, we investigated the association between high uptake in noncancerous lung (NCL) on 18 F- FDG-PET/CT and ICI-ILD in lung cancer., Methods: Patients with primary lung cancer who underwent FDG-PET/CT within three months prior to ICI therapy were retrospectively included. Artificial intelligence was utilized for extracting the NCL regions (background lung) from the lung contralateral to the primary tumor. FDG uptake by the NCL was assessed via the SUVmax (NCL-SUVmax), SUVmean (NCL-SUVmean), and total glycolytic activity (NCL-TGA)defined as NCL-SUVmean×NCL volume [mL]. NCL-SUVmean and NCL-TGA were calculated using the following four SUV thresholds: 0.5, 1.0, 1.5, and 2.0., Results: Of the 165 patients, 28 (17.0%) developed ILD. Univariate analysis showed that high values of NCL-SUVmax, NCL-SUVmean 2.0 (SUV threshold=2.0), and NCL-TGA 1.0 (SUV threshold=1.0) were significantly associated with ILD onset (all p = 0.003). Multivariate analysis adjusted for age, tumor FDG uptake, and pre-existing interstitial lung abnormalities revealed that a high NCL-TGA 1.0 (≥149.45) was independently associated with ILD onset (odds ratio, 6.588; p = 0.002). Two-year cumulative incidence of ILD was significantly higher in the high NCL-TGA 1.0 group than in the low group (58.4% vs. 14.4%; p < 0.001)., Conclusion: High uptake of NCL on FDG-PET/CT is correlated with ICI-ILD development, which could serve as a risk stratification tool before ICI therapy in primary lung cancer., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Satoshi Watanabe reports: grants from Boehringer Ingelheim and Nippon Kayaku; lecture fees and speakers bureaus from AstraZeneca, Lilly, Chugai Pharma, Bristol-Myers, Novartis Pharma, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Nippon Kayaku, Kyowa Hakko Kirin, Merck, Takeda Pharmaceutical and Celltrion, all outside the submitted work. Dr. Naohiro Yanagimura reports: lecture fees and speakers bureaus from MSD K.K and Honoraria, all outside the submitted work. Dr. Masashi Arita reports: lecture fees and speakers bureaus from Chugai Pharma, all outside the submitted work. Dr. Tomohiro Tanaka reports: lecture fees and speakers bureaus from Chugai and Takeda, all outside the submitted work. Dr. Koichiro Nozaki reports: lecture fees and speakers bureaus from AstraZeneca, Bristol-Myers, MSD, Taiho Pharmaceutical, Ono Pharmaceutical, and Chugai Pharmaceutical Co, all outside the submitted work. Dr. Yu Saida reports: lecture fees and speakers bureaus from Chugai, Lilly, Astra Zeneca, and Ono, all outside the submitted work. Dr. Toshiaki Kikuchi reports: grants from Nobelpharma, Boehringer Ingelheim, Taiho Pharmaceutical, KYORIN Pharmaceutical, Shionogi Pharma, Chugai Pharma, Asahi Kasei, Daiichi Sankyo, Nippon Kayaku and TEIJIN PHARMA; consulting fees from AN2 Therapeutics; lecture fees and speakers bureaus from Viatris, Astellas Pharma, Insmed, Boehringer Ingelheim, Terumo, Lilly, AstraZeneca, Daiichi Sankyo, KYORIN Pharmaceutical, Novartis Pharma, Merck, Bristol-Myers, NIPRO, Eisai, Ono Pharmaceutical, Chugai Pharma, GSK, Sumitomo Pharma, Kyowa Hakko Kirin, MSD, Sanofi, Shionogi Pharma, Meiji Seika Pharma and Taiho Pharmaceutical, all outside the submitted work. Dr. Hiroyuki Ishikawa reports: grants from Daiichi Sankyo, GE Healthcare Pharma, Guerbet, Nihon Medi-Physics, and PDRadiopharma; lecture fees from Bayer, Boehringer Ingelheim, Canon, Chugai Pharma, Eisai, FUJIFILM Medical, GE Healthcare Pharma, and Nihon Medi-Physics, all outside the submitted work. The remaining authors declare no conflict of interest., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)