PURPOSE: Colorectal liver metastases (CRLM) pose a significant clinical challenge due to their high recurrence rates, even after surgical resection. There is an urgent need for reliable prognostic biomarkers to improve risk stratification and guide treatment decisions for CRLM patients. METHODS/PATIENTS: In this study, we performed whole-exome sequencing (WES) on 57 CRLM patients and conducted a comparative genomic analysis of primary tumors and matched liver metastases in 8 patients. We systematically identified prognostic factors associated with overall survival (OS) and developed a predictive nomogram for CRLM patients. RESULTS AND CONCLUSIONS: The most frequently mutated genes in our cohort were APC (64.91%) and TP53 (64.91%), followed by KRAS (50.88%), PIK3CA (24.56%), and SMAD4 (24.56%). Pathway analysis revealed significant enrichment in p53, IGF, and Ras signaling pathways. Notably, primary and metastatic lesions exhibited high mutational concordance. Multivariate analysis identified five independent prognostic factors for OS: number of metastasis-positive lymph node stations in primary resected tumor tissue, mutational status of ZNF717 and MUC2, APC mutation status, and chr9p13.3 amplification. The nomogram integrating these factors achieved a C index of 0.798 for OS prediction. Our findings suggest that integrating genomic profiling into clinical practice could enhance prognostic assessment and optimize treatment stratification for CRLM patients.