Background: Recent data suggests a role for immune-checkpoint inhibition in the management of intrahepatic cholangiocarcinoma (iCCA). Chromosomal 9p21 loss with CDKN2A/MTAP co-deletion commonly occurs in iCCA and may correlate with poor response to immunotherapy. Methods: 2,508 cases of intrahepatic cholangiocarcinoma underwent comprehensive genomic profiling with the FoundationOne CDx assay. PD-L1 expression was measured with IHC using the Dako 22C3 antibody and measured with the tumor proportion score (TPS) method. Prevalence of different selected genomic alterations in tumors with MTAP loss was compared against MTAP intact tumors using Fischer’s exact test. Results: In 2,508 cases analyzed, 15.5% of tumors were found to have MTAP loss. Of these, 98.7% had concomitant CDKN2A and 9p21 loss. No significant difference in immune biomarkers in MTAP loss versus wildtype (WT) was seen. PD-L1 low positive at 13.2% vs 19.2%, PD-L1 high positive at 2.9% vs 6.5%, median tumor mutational burden at 2.5 vs 2.5 and MSI high at 0.0% vs 1.6% in MTAP loss vs WT, respectively. There were no significant differences between MTAP loss and WT in potentially actionable mutations including FGFR1/2 mutations (12.4% vs 10.7%), PIK3CA (6.40% vs 6.60%), ERBB2 (4.10% vs 5.30%) and KRAS G12C (1.20% vs 1.10%) in MTAP loss vs WT, respectively. The table depicts significant genomic differences between these subgroups. Conclusions: This represents the largest iCCA cohort with MTAP loss to our knowledge. Given the historical data regarding 9p21 loss and poor response to immunotherapy, efforts targeting MTAP loss through synthetic lethality or other novel combinational therapeutics are justified.