Background <p>This study aimed to identify predictive factors for chemotherapy response in colorectal liver metastasis (CRLM) patients.</p> Methods <p>Eligible participants with CRLM who had undergone at least two systemic chemotherapy cycles postdiagnosis were retrospectively analyzed. They were categorized as responders and nonresponders based on tumor size reduction. DNA extracted from tumor tissues was subjected to sequencing. Additionally, a comparative analysis of oncogenic pathways was conducted. Logistic regression analysis was conducted to determine predictive factors for chemotherapy response.</p> Results <p>A total of 230 Chinese patients were analyzed. Significant differences in mutation distribution were found, particularly in the KRAS gene and several specific rare gene mutations (EP300, PTPRK, KMT2A, and ACVR1B), as well as in the PI3K and RTK-RAS pathways between the two groups. Gender, utilization of biological targeted agents (BTAs), KRAS gene mutations, PI3K pathway alterations, and specific rare gene mutations were used to construct a specific efficacy prediction model, achieving an area under the curve (AUC) of 0.73. Approximately 75% (87/116) of patients could potentially avoid BTAs based on the model’s predictions. In a subgroup of 52 patients not using BTAs, simulation indicated that 10 patients could benefit by including BTAs, representing 32% (10 of 31) of initially nonresponsive patients.</p> Conclusions <p>Gender, utilization of BTAs, and specific gene and pathway mutations may be significant predictors of chemotherapy response in CRLM patients. These findings highlight the role of genetic profiling in refining treatment strategies.</p>