479 Background: Pre and post-operative elevation of serum CA 19-9 have been associated with poor outcomes and increased risk of recurrence in patients with resected intrahepatic cholangiocarcinoma (ICC). We sought to investigate the impact of CA 19-9 response and dynamics on survival for patients with ICC undergoing surgical resection. Methods: Clinicopathologic characteristics were abstracted from a prospectively maintained database at a tertiary cancer care center for patients with ICC undergoing surgical resection from 2003 to 2020. Exclusion criteria included CA 19-9 non-producers (≤ 1 U/mL at baseline), missing baseline/pre-operative or postoperative CA 19-9 value, or total bilirubin > 2 mg/dL. Overall (OS) and recurrence-free survival (RFS) was compared among patients when categorized by baseline (neoadjuvant)/pre-operative (upfront surgery) and post-operative CA 19-9 values: normal (> 1 to 37 U/mL), intermediate (> 37 to 200 U/mL), and elevated (> 200 U/mL). Patients were then stratified by perioperative CA 19-9 response (responder [non-normal to normal CA 19-9 OR 50% reduction in CA 19-9; normal to normal CA 19-9], non-responder [non-normal to non-normal CA 19-9 OR < 50% reduction in CA 19-9; normal to non-normal CA 19-9]) and CA 19-9 dynamics (normal to normal, non-normal to normal, non-normal to non-normal, normal to non-normal CA 19-9 values). Results: A total of 112 patients were identified including 67 (59.8%) who underwent upfront surgery and 45 (40.2%) who received neoadjuvant therapy. Patients with a normal CA 19-9 at diagnosis had median RFS and OS durations of 61 and 163 months, followed by intermediate CA 19-9 (20 and 98 months) and elevated CA 19-9 (18 and 46 months, p = 0.308 RFS; p = 0.295 OS). Those who had a normal CA 19-9 post-operatively had the best median RFS and OS (46 and 163 months), followed by intermediate CA 19-9 (13 and 58 months) and elevated CA 19-9 (5 and 8 months, p = 0.059 RFS; p = 0.005 OS). When stratified by perioperative CA 19-9 response, responders had a median RFS of 36 vs. 13 months in non-responders (p = 0.143), and a median OS of 98 months vs. 88 months in non-responders (p = 0.077). Patients with normal CA 19-9 post-operatively had longer RFS/OS (normal to normal, 48/98 months; non-normal to normal, 30/not estimable months) than those who had non-normal CA 19-9 both pre- and post-operatively (non-normal to non-normal, 7/34 months, p = 0.018 RFS; p = 0.007 OS). Conclusions: Patients with normal CA 19-9 levels post-operatively, who had either normal or elevated CA 19-9 pre-operatively, had the greatest RFS and OS durations. A normal (or normalized) post-operative CA 19-9 may inform patient-centered decisions on adjuvant therapy and/or surveillance intensity.