BACKGROUND: The prognostic factors at mutational and transcriptional levels are not clear for stage IV colorectal cancer (CRC) patients with liver metastasis who undergo primary cancer palliative surgery with post-surgical adjuvant therapy. We aimed to establish and validate models for predicting the prognosis of these patients by combining mutational, transcriptional and clinicopathological information. METHODS: Data of 45 stage IV CRC patients with liver metastasis were downloaded from the cBioportal database as the training cohort. Another 30 patients from our hospital were retrospectively recruited as the external validation cohort. Patients were followed up to 4,699 days (median: 823 days) and 2,380 days (median: 980 days) for the overall survival (OS) in the training and validation cohort, respectively. Patients were followed up to 4,699 days (median: 264 days) and 2,259 days (median: 272 days) for the progression-free survival (PFS) in the training and validation cohort, respectively. Tissue samples of the primary CRC were collected and sequenced. Data were analyzed and figures were plotted using the R software. RESULTS: The mutational and transcriptional alterations and their features were characterized. CONCLUSIONS: The prognostic factors for stage IV CRC patients with liver metastasis were identified. Models for predicting the OS and PFS were successfully established and validated. The models may help to establish the personalized therapeutic strategies before treatment.