Researchers sought to characterize the immunogenomic and epigenomic heterogeneity of multifocal ICC to guide treatment decisions for a study. However, little is known about multifocal ICC intratumor heterogeneity (ITH) and how it affects the patient’s response to these treatments. Researchers collected 66 tumor samples from 16 patients with multifocal ICC. They used whole-exome sequencing, bulk and single-cell RNA sequencing, methylation microarrays, and multiplex immunostaining to characterize the tumor and immune heterogeneity. Patients were divided into high- or low-ITH groups according to the median ITH index. The findings were validated using 2 independent cohorts. In addition, anti-PD-1 therapy responses were evaluated. Multifocal ICC in a patient with high ITH revealed significant intratumor genomic, transcriptional, and epigenomic heterogeneity. The immune profile of multiple tumors within a patient was less heterogeneous in the high- or low-ITH groups, and multiple tumors responded consistently to anti-PD-1 immunotherapy. Unsupervised immune marker clustering identified 1 low and 1 high immune subtype, with the high immune subtype having higher immune cell infiltration, closer tumor-immune cell interactions, and upregulated IFN-signature expression. Determining CD8B and ICOS expression levels aided in immune classification and prediction of patient prognosis. Finally, by regulating immune-gene expression, promoter DNA methylation contributed to the different immune profiles of the 2 subtypes. The genome, transcriptome, and epigenome of multifocal ICC were highly heterogeneous. Researchers proposed an immune classification that stratified patients’ prognosis and may support personalized immunotherapy based on ICC’s less heterogeneous immune profile.