Background: The BILCAP clinical trial established adjuvant capecitabine as the standard of care treatment in patients with resected biliary tract cancer. Translational work to investigate the role of cancer driver genes and other potentially targetable mutations in patients enrolled on BILCAP was performed, with this analysis focusing on patients with intrahepatic cholangiocarcinoma (iCCA). Methods: Archived fixed formalin (FFPE) tissue samples were collected from consented BILCAP patients. These samples underwent DNA and RNA extraction followed by low-pass whole genome sequencing (lp-WGS), targeted gene sequencing (TGS) and RNA sequencing (RNAseq) for copy number (CN) analysis, mutation analysis and gene fusion analysis. Results: 84 of the 447 BILCAP patients had iCCA; 45 successfully underwent lp-WGS and RNAseq, of whom 36 also underwent TGS. The median age was 61 years (95% CI 57.8 – 64.2), 55.6% were female and 23 received capecitabine (51.1%). FGFR2 gene fusions were present in 9 patients (20.0%), as were fusions in NTRK1 (n = 3, 6.7%), FGFR1 (n = 3, 6.7%), FGFR3 (n = 2, 4.4%) and FGFR4 (n = 2, 4.4%). Commonly mutated driver genes included ROS1 (n = 12, 33.3%), MET (n = 10, 27.8%) and ALK (n = 7, 19.4%) with known pathogenic variants seen in IDH1 (n = 4, 11.1%; total number of mutations = 7, 19.4%), BRAF (n = 2, 5.6%; total n = 6, 16.7%), FGFR2 (n = 1, 2.7%; total n = 8, 22.2%), FGFR3 (n = 1, 2.7%, total n = 6, 16.7%) , IDH2 (n = 1, 2.7%; total n = 6, 16.7%) and EGFR (n = 1, 2.7%; total n = 4, 11.1%). Commonly amplified (CN ≥ 4, ploidy < 3) genes included NTRK1 (n = 9, 20.0%), ERBB2 (n = 8, 17.8%), and MET (n = 3, 6.7%). Most of the alterations investigated in this cohort did not significantly affect recurrence risk or overall survival (OS), including FGFR2 fusions (OS HR 1.23, p = 0.695; recurrence HR 1.32 p = 0.555). However, the presence of a FGFR3 fusion gene significantly reduced OS (OS HR 6.57, p = 0.0091; recurrence HR 3.71, p = 0.0734), and having ≥ 4 copies of either NTRK1 (OS HR 3.55, p = 0.0027; recurrence HR 3.48, p = 0.0019) or MET (OS HR 6.06, p < 0.001; recurrence HR 6.05 p < 0.001) significantly reduced OS and increased the risk of recurrence. Conclusions: The BILCAP cohort shows a wide variety of driver and potentially targetable mutations in unselected iCCA patients, comparable to previous early-stage biliary tract cancer datasets. Of note, patients with FGFR3 fusions, MET amplification or NTRK1 amplification had significantly shorter OS, and patients with MET or NTRK1 amplification had significantly reduced OS and significantly increased risk of disease recurrence. MET amplification, NTRK1 amplification and FGFR3 fusions may be important indicators in determining prognosis, and could provide attractive targets for future targeted anti-cancer therapy in iCCA. Clinical trial information: EUCTR2005-003318-13.