Background: IL-6 is an inflammatory cytokine that modulates growth and differentiation of tumor cells. The role of IL-6 as a biomarker in this cancer subset population remains questionable. We aimed to study IL-6 levels in patients with hepatobiliary cancer and the associated patient characteristics. Methods: Stored serum from 91 patients with treatment-naïve hepatobiliary cancers (hepatocellular carcinoma, gallbladder cancer, intra- and extra-hepatic cholangiocarcinoma) were measured for IL-6 levels. Demographics and clinical parameters were collected from retrospective chart review. IL-6 was measured in stored serum from 91 controls, matched for age, gender and BMI. Associations between baseline covariates and IL6 measurements and differences in Overall Survival (OS) were assessed using Accelerated Failure Time (AFT) models. P-values <0.05 were considered statistically significant. All data analyses were generated using SAS/STAT software, Version 9.4. Results: A total of 91 cases+91 controls were analyzed: 68% males in each set. IL-6 levels were significantly higher in the cases than the controls [median: 15.2pg/ml vs 1.7pg/ml p<0.01]. Amongst cancer patients the following elements were associated with significantly higher levels of IL-6: cirrhosis (AF=3.18 p<0.01), uncontrolled pain (AF=1.97 p<0.01), worse ECOG status (p<0.01) and portal vein thrombosis (AF=1.57, p=0.03). A 3-fold increase in Alpha fetoprotein (AFP) corresponded with a 9% increase in IL-6 (AF=1.09, p=0.015). IL-6 appeared to be modestly higher in males [median: 4.47 vs 5.32 p=0.5]. IL-6 remained an independent predictor of OS after controlling for several possible confounders (AFP, Cirrhosis, portal vein thrombosis). Each 10-unit increase in IL-6 resulted in an 8% reduction in the time to death (AF=0.92 (95% CI:0.78 to 1.00) p=0.033). Conclusions: IL-6 levels are significantly elevated in hepatobiliary cancers, directly correlating with AFP. Higher IL-6 levels are associated with aggressive tumors and poorer survival. These findings suggests the potential prognostic/predictive value of IL-6 and should initiate early palliative care referrals. Anti-IL6 therapy could increase meaningful survival time for patients.