Background: The objective of the current study was to assess the impact of serum CA19-9 and CEA and their combination on survival among patients undergoing surgery for intrahepatic cholangiocarcinoma (ICC). Methods: Patients who underwent curative-intent resection of ICC between 1990 and 2016 were identified using a multi-institutional database. Patients were categorized into four groups based on combinations of serum CA19-9 and CEA (low vs. high). Factors associated with 1-year mortality after hepatectomy were examined. Results: Among 588 patients, 5-year OS was considerably better among patients with low CA19-9/low CEA (54.5%) compared with low CA19-9/high CEA (14.6%), high CA19-9/low CEA (10.0%), or high CA19-9/high CEA (0%) (P < 0.001). No difference in 1-year OS existed between patients who had either high CA19-9 (high CA19-9/low CEA: 70.4%) or high CEA levels (low CA19-9/high CEA: 72.5%) (P = 0.92). Although patients with the most favorable tumor marker profile (low CA19-9/low CEA) had the best 1-year survival (87.9%), 15.1% (n = 39) still died within a year of surgery. Among patients with low CA19-9/low CEA, a high neutrophil-to-lymphocyte ratio (NLR) (odds ratio 1.09; 95% confidence interval 1.03-1.64) and large size tumor (odds ratio 3.34; 95% confidence interval 1.40–8.10) were associated with 1-year mortality (P < 0.05). Conclusions: Patients with either a high CA19-9 and/or high CEA had poor 1-year survival. High NLR and large tumor size were associated with a greater risk of 1-year mortality among patients with favorable tumor marker profile.