Background: CCA is a rare, heterogeneous malignancy with poor prognosis due to late onset of symptoms and relative resistance to available therapies. FGFR2 fusions are common, occurring in 10–16% of intrahepatic CCA (iCCA). There is increasing awareness of the importance of molecular profiling to inform treatment choices, although real-world data (RWD) are lacking on the natural history of pts with CCA and FGFR2 fusions/rearrangements receiving therapies for advanced disease. This retrospective, observational, natural history study used a nationwide (US-based) de-identified clinico-genomic database (CGDB) to compare overall survival (OS) in pts with advanced CCA and FGFR2 fusions/rearrangements vs. those with wild-type (WT) FGFR2. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine CCA CGDB (FH-FMI-CGDB). The data originated from approximately 280 US cancer clinics (̃800 sites of care). Pts were ≥18y of age, had chart-confirmed advanced CCA, comprehensive genomic profiling, and ≥2 visits within the Flatiron Health network since Jan 1, 2011. Primary objective: evaluate OS in pts with FGFR2 fusions/rearrangements and WT FGFR2 from the index date (date of diagnosis of advanced CCA) to date of death from any cause. A key secondary objective was to evaluate the influence of FGFR status on OS after adjusting for potential prognostic variables. Risk-set adjustment was used to account for left truncation for all time-to-event analyses. Results: As of May 2020, 571 pts from the CCA FH-FMI-CGDB met the inclusion criteria; 75 pts with FGFR2 fusions/rearrangements (median age 63y; 64% female; 95% iCCA; 68% stage IV at initial diagnosis), and 496 pts FGFR2 WT (median age 65y; 48% female; 74% iCCA; 55% stage IV at initial diagnosis). Median OS was numerically higher, but not statistically different, for pts with FGFR2 fusions/rearrangements vs FGFR2 WT (12.1m [95% CI 8.5−17.1] vs 7.1m [95% CI 5.7−8.8]; log rank p = 0.184). Median OS was also numerically higher, but not statistically different, for FGFR2 fusions/rearrangements vs FGFR WT in the subset of 437 pts with iCCA (12.1m [95% CI 8.4−17.1] vs 7.8m [95% CI 6.1−10.0]; log rank p = 0.375). FGFR2 status was not a significant factor contributing to OS in univariate, bivariate, or multivariate models after adjusting for potential prognostic covariates. Conclusions: This analysis of RWD did not demonstrate a clear survival advantage for pts with FGFR2 fusions/rearrangements vs FGFR2 WT CCA receiving therapies for advanced disease, although a non-significant trend towards longer OS was observed in pts with FGFR2 fusions/rearrangements. FGFR2 status was not a significant predictor of OS after adjusting for potential prognostic covariates. An additional sub-analysis is ongoing to determine OS from time of initiation of second-line therapy in pts with FGFR2 fusions/rearrangements.