For a study, the researchers sought to see if genomic risk groups discovered by colorectal liver metastasis (CRLM) somatic mutation testing may be used for “molecularly-guided” adjuvant systemic chemotherapy and hepatic artery infusion of FUDR (SYS+HAI-FUDR). A prospective institutional database was analyzed for consecutive patients with resected CRLM and available mutational characterization using Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets. Based on previously established changes in SMAD4, EGFR, and the RAS/RAF pathway, patients were divided into 3 genetic risk categories. Cox proportional hazard regression and propensity score-matched analyses were used to assess the relationship between SYS+HAI-FUDR and overall survival compared to adjuvant chemotherapy alone (SYS) in each genetic risk group. There were 334 patients in total (SYS+HAI-FUDR 204; SYS 130), with RAS/RAF changes and SMAD4 inactivation rates of 47.4% and 11.7%, respectively. Adjuvant SYS+HAI-FUDR was associated with a lower risk of death (HR 0.50, 95% CI 0.26–0.98, P=0.045) in the low-risk genomic group, but not in the moderate-risk (HR 1.07, 95%  CI 0.5–2.07, P=0.749) or high-risk (HR 1.62, 95% CI 0.29–9.12, P=0.537) cohorts after a median follow-up of 58 Adjuvant SYS+HAI-FUDR remained related with significant increases in long-term survival in the low-risk genomic cohort after propensity score matching (5-year actuarial survival: 89% vs 68%, P=0.019). RAS/RAF, SMAD4, and EGFR mutations may be relevant in guiding treatment selection in resectable CRLM patients, and they should be externally validated and integrated into future clinical trial design.