Background: Despite advances in systemic therapy for unresectable ICC, median survival remains less than 12 months (mo). HAI FUDR alone and combination systemic therapy both have activity in these patients. This trial investigated HAI FUDR/Dex plus GemOx. Methods: Thirty nine patients (pts) with unresectable ICC were enrolled at two institutions between 2013-17. Pts were treated with HAI FUDR and GemOx every 2 weeks. Progression-free survival (PFS) was calculated from date of HAI to progression of disease (POD) or death and compared to historical controls. Secondary outcomes included overall survival (OS), conversion to resection, response rates, and toxicity. PFS and OS were estimated using Kaplan-Meier methods. Twenty nine pts from MSK underwent targeted next generation tumor sequencing of > 400 genes (MSK-IMPACT). Results: Median age was 61 (range 38-80), 13 (33%) male. The median PFS was 11.5 mo, (90% CI:9.7mo), exceeding the historical controls of 6-8 mo. Eighteen pts (46%) had partial response (PR) and 20 (51%) had stable disease (SD), for a 97% disease control (PR+SD) rate. Three pts were converted to resectability and were censored at 12, 12 and 16 mo, respectively. Four pts (10%) had grade 4 toxicities requiring removal from the study, including portal hypertension, GDA aneurysm and GDA extravasation related to HAI catheter, and hyperbilirubinemia. The most common grade 3 toxicities were elevated liver enzymes (ALT 54%, AST 33% and bilirubin 18%), abdominal pain 13% and anemia 12%. At a median follow up of 17 mo, the 1 year OS was 86.4% [95%CI:70-94%] and the 2 year OS was 53% [95%CI: 32%-69%]. Most prevalent mutations were IDH1/2 ( 9/26, 34.6%), BAP1 (8/26, 30.7%), TP53 (4/26, 15.3%). IDH1/2 mutations were associated with OS benefit (p = 0.018). Conclusions: Combined HAI FUDR plus GemOx is effective therapy for unresectable ICC due to its high rate of tumor response and control, PFS benefit, and manageable toxicities. The regimen warrants further investigation in a randomized trial. Clinical trial information: NCT01862315