Background: The incidence and mortality of ICC is rising in the U.S. While surgical resection currently offers the only potential for cure, the role of adjuvant chemotherapy is not well defined. Tumor genomic profiling is increasingly used to make adjuvant therapy decisions for malignancies. The purpose of this project was to evaluate the correlation between tumor genomic profile and the ability of adjuvant chemotherapy to prevent ICC recurrence after resection. Methods: A retrospective review of 49 patients with ICC undergoing surgical resection and comprehensive tumor genomic profiling was performed. The median age at diagnosis was 56 years (range: 21-72 yrs), 67% were female, and 67% were Caucasian. At resection, 20% had stage I disease, 43% stage II, 29% stage III, and 8% stage IV. Over 90% had moderately or poorly differentiated adenocarcinoma. Clinically relevant genetic mutations (those targeted by anticancer drugs currently on the market or required for entry into a mechanism-driven clinical trial) were evaluated using Foundation Medicine testing. Results: The median recurrence free survival (RFS) for the entire cohort was 9 months (range: 1-55 mo). 59% of patients received adjuvant chemotherapy – 66% gemcitabine-based treatment and 31% capecitabine-based. The most prevalent mutations were FGFR2 (28%), CDKN2A/B (24%), IDH1 (17%), and ARID1A (17%). Median RFS for the adjuvantly treated group was 12 months (range: 3-55 mo), and the presence of any clinically relevant mutation was associated with worse RFS (x vs. y, p = 0.03). IDH1 (30%), BAP1 (25%), and PBRM1 (20%) were most frequently mutated amongst patients who did not receive adjuvant therapy, and their median RFS was 5 months (range: 1-54 mo). Lack of an IDH1 mutation correlated with worse RFS (p = 0.02), while lower stage correlated with improved RFS (p = 0.01). Conclusions: For patients with ICC undergoing resection and adjuvant chemotherapy, the presence of clinically relevant genetic mutations is associated with reduced RFS. To gain further insight into the influence of tumor genomic profile on the effectiveness of adjuvant chemotherapy for this patient population, a multicenter collaborative effort is needed.