BackgroundChronic　thromboembolic　pulmonary　hypertension　(CTEPH)　is　a　severely　progressive　disease　that　leads　to　right　heart　failure　and　death.　Previous　studies　have　shown　that　diabetes　and　insulin　resistance　(IR)　are　closely　related　to　pulmonary　hypertension,　but　the　role　of　IR　in　patients　with　CTEPH　remains　unexplored.　In　this　study,　we　investigated　the　relationship　between　four　insulin　resistance　indices　and　disease　severity,　hemodynamic　parameters,　and　adverse　outcomes　in　patients　with　CTEPH.MethodsWe　conducted　a　multicenter,　retrospective　cohort　study　involving　516　patients　diagnosed　with　CTEPH　between　January　2013　and　December　2022.　The　metabolic　score　for　IR　(METS-IR),　triglyceride　to　high-density　lipoprotein　cholesterol　(TG/HDL-C)　ratio,　triglyceride　and　glucose　(TyG)　index,　and　triglyceride-glucose-body　mass　(TyG-BMI)　index　were　used　to　quantify　IR　levels　in　patients　with　CTEPH.　The　primary　endpoint　events　were　clinical　worsening.　Multivariable　Cox　regression,　restricted　cubic　splines,　and　receiver　operating　characteristic　analyses　were　used　to　evaluate　the　predictive　value　of　surrogates　for　IR.ResultsCompared　with　in　low　to　intermediate-low　risk　patients,　the　METS-IR　(36.2　+/-　6.7　vs.　37.7　+/-　8.7,　p　=　0.038)　and　TyG-BMI　index　(204.0　+/-　36.2　vs.　212.6　+/-　46.5,　p　=　0.022)　were　significantly　increased　in　high　to　intermediate-high　risk　patients.　METS-IR　correlated　with　markers　of　disease　severity,　such　as　World　Health　Organization　functional　class,　6-minute　walk　distance,　and　N-terminal　pro-brain　natriuretic　peptide　levels.　During　a　mean　of　2.5　years＇　follow-up,　110　participants　experienced　all-cause　death　or　worsening　condition.　METS-IR　independently　predicted　clinical　worsening　(hazard　ratio:　1.27;　95%　confidence　interval　1.06-1.53　per　1.0-standard　deviation　increment,　p　=　0.009)　after　fully　adjusting　for　covariates.　Adding　METS-IR　to　the　COMPERA　2.0　risk　score　significantly　improved　its　predictive　ability,　reclassification　and　discrimination　ability.ConclusionsMETS-IR　is　an　independent　predictor　of　clinical　worsening　in　patients　with　CTEPH.　It　offers　a　convenient　marker　for　assessing　disease　severity　and　long-term　outcomes　in　clinical　risk　assessment.