Metastatic progression of colorectal adenocarcinoma (CRC) remains poorly understood and poses significant challenges for treatment. To overcome these challenges, we performed multiomics analyses of primary CRC and liver metastases. Genomic alterations, such as structural variants or copy number alterations, were enriched in oncogenes and tumor suppressor genes and increased in metastases. Unsupervised mass spectrometry-based proteomics of 135 primary and 123 metastatic CRCs uncovered distinct proteomic subtypes, three each for primary and metastatic CRCs, respectively. Integrated analyses revealed that hypoxia, stemness, and immune signatures characterize these 6 subtypes. Hypoxic CRC harbors high epithelial-to-mesenchymal transition features and metabolic adaptation. CRC with a stemness signature shows high oncogenic pathway activation and alternative telomere lengthening (ALT) phenotype, especially in metastatic lesions. Tumor microenvironment analysis shows immune evasion via modulation of major histocompatibility complex (MHC) class I/II and antigen processing pathways. This study characterizes both primary and metastatic CRCs and provides a large proteogenomics dataset of metastatic progression. Display omitted •Distinct proteogenomic subtypes of colorectal cancer characterize primaries and metastases•A hypoxic signature was enriched in metastases along with metabolic reprogramming•A cancer stemness signature with ALT feature was elevated in metastases•Immune-cold cancer showed suppression of antigen presentation, especially in metastases Tanaka et al. conduct proteogenomic characterization of 154 primary and 142 metastatic colorectal cancers and find 6 subtypes with 3 functional signatures (hypoxia, stemness, and immune). These subtypes shed light on the molecular progression from primary to metastatic cancer, highlighting proteomic plasticity and features of metastatic disease.