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Purpose: Clinical-pathologic features and natural history of patients with isocitrate dehydrogenase ( IDH )-mutant intrahepatic cholangiocarcinoma (CCA) are not well characterized. Here, we sought to describe the natural history, clinical phenotype, and prognostic impact of advanced, IDH -mutated CCA., Methods: We conducted a multicentric, retrospective analysis of patients with IDH -mutated (IDH1 or IDH2) CCA between 2010 and 2020. Median overall survival (OS) and progression-free survival (PFS) analyses were performed using the Kaplan-Meier method. Chi-square test was used to analyze disease control rate (DCR) and overall response rate (ORR). Matched controls were used for comparing survival between patients with and without IDH mutations (mIDH)., Results: Sixty-five patients with IDH -mutated CCA were included. All patients had intrahepatic CCA. On first-line chemotherapy, median OS and median PFS were 21.2 months and 8.3 months, respectively. Notably, median OS (32.4 v 19.5 months, P = .12) and PFS (18.0 v 8.0 months, P = .12) were not significantly affected by disease status at presentation (locally advanced v metastatic, respectively). Median OS was significantly longer in patients with mIDH (21.2 v 10.5 months; P < .01). First-line gemcitabine-containing regimens had a significantly higher DCR and ORR than non-gemcitabine-containing regimens (DCR: 75% v 33%, P = .01; ORR: 39% v 0%, P = .02). In patients receiving IDH inhibitor therapy, median PFS was 4.6 months with a DCR of 29%., Conclusion: CCA with m IDH confers a unique subtype resulting in a better survival compared with that of counterparts. IDH inhibitors represent a promising therapeutic option in later lines of therapy in this subgroup., Competing Interests: Qian ShiStock and Other Ownership Interests: Amgen, Johnson & Johnson, MerckHonoraria: Chugai PharmaConsulting or Advisory Role: Yiviva, Boehringer Ingelheim, Regeneron, Hoosier Cancer Research NetworkResearch Funding: Celgene (Inst), Roche/Genentech (Inst), Janssen (Inst), BMS (Inst), Novartis (Inst) Nguyen TranHonoraria: QED Therapeutics (Inst)Consulting or Advisory Role: QED Therapeutics (Inst) Kabir ModyStock and Other Ownership Interests: CytoDyn, OncotherapeuticsConsulting or Advisory Role: Celgene, Genentech/Roche, Merrimack, Eisai, AstraZeneca, Vicus Therapeutics, Ipsen, Boston Scientific, BTG, Exelixis, Incyte (Inst), QED TherapeuticsResearch Funding: FibroGen (Inst), Senhwa Biosciences (Inst), ARIAD (Inst), TRACON Pharma (Inst), MedImmune (Inst), Agios (Inst), ArQule (Inst), Taiho Pharmaceutical (Inst), Gritstone Oncology (Inst), Incyte (Inst), Merck (Inst), Vyriad (Inst), Turnstone Bio (Inst), AstraZeneca (Inst), Basilea (Inst) Daniel AhnStock and Other Ownership Interests: NateraConsulting or Advisory Role: Eisai, Exelixis, Genentech/Roche, Advanced Accelerator ApplicationsResearch Funding: Bayer, AstraZeneca Mitesh BoradStock and Other Ownership Interests: Gilead Sciences, AVEO, Intercept Pharmaceuticals, Spectrum PharmaceuticalsConsulting or Advisory Role: G1 Therapeutics, Fujifilm (Inst), Agios (Inst), Insys Therapeutics (Inst), Novartis (Inst), ArQule (Inst), Celgene (Inst), Inspyr Therapeutics, Halozyme (Inst), Pieris Pharmaceuticals (Inst), Taiho Pharmaceutical (Inst), Immunovative Therapies, Exelixis, Lynx Group, Genentech, Western Oncolytics, Klus Pharma, De Novo Pharmaceuticals, Merck, ImvaxResearch Funding: Boston Biomedical (Inst), miRNA Therapeutics (Inst), Senhwa Biosciences (Inst), MedImmune (Inst), BiolineRx (Inst), Agios (Inst), Halozyme (Inst), Celgene (Inst), Threshold Pharmaceuticals (Inst), Toray Industries (Inst), Dicerna (Inst), Sillajen (Inst), Eisai (Inst), Taiho Pharmaceutical (Inst), EMD Serono (Inst), Isis Pharmaceuticals (Inst), Incyte (Inst), Sun Biopharma (Inst), ARIAD (Inst), ImClone Systems (Inst), QED Therapeutics (Inst), Puma Biotechnology (Inst), Adaptimmune (Inst), Merck Serono (Inst), RedHill Biopharma (Inst), Basilea (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: ArQule, Celgene, AstraZeneca Tanios Bekaii-SaabConsulting or Advisory Role: Amgen (Inst), Ipsen (Inst), Lilly (Inst), Bayer (Inst), Roche/Genentech (Inst), AbbVie, Incyte (Inst), Immuneering, Seattle Genetics (Inst), Pfizer (Inst), Boehringer Ingelheim, Janssen, Eisai, Daiichi Sankyo/UCB Japan, AstraZeneca, Exact Sciences, Natera, Treos Bio, Celularity, SOBI, BeiGene, Foundation MedicinePatents, Royalties, Other Intellectual Property: Patent WO/2018/183488, Patent WO/2019/055687Other Relationship: Exelixis, Merck (Inst), AstraZeneca, Lilly, Pancreatic Cancer Action Network Amit MahipalHonoraria: EisaiConsulting or Advisory Role: QED TherapeuticsResearch Funding: Taiho PharmaceuticalNo other potential conflicts of interest were reported.