Background: Somatic gene mutations have been suggested to impact survival following resection of colorectal liver metastases (CRLM). However, most studies included a selected population with known mutation data and did not employ homogeneous methods. This study aimed to determine the prognostic impact of somatic gene mutations and microsatellite instability (MSI) in CRLM using a standardized protocol and assess their survival effects according to primary tumor location. Methods: A total of 568 patients who underwent resection of CRLM during 2001-2014 were identified from a prospectively maintained registry of the National Cancer Center. MassARRAY based mutation profiling of cancer-related genes (KRAS, NRAS, HRAS, BRAF, PIK3CA, MET, PTEN, APC, TP53)/MSI analysis was made in primary tumors from 538 (94.7%)/526 (92.6%) patients. Results: Primary tumor locations were: right colon for 51 (9.0%); transverse colon for 42 (7.4%); left colon for 238 (34.5%); rectum for 279 (49.1%) patients. Right sided tumors were associated shorter overall survival (OS) after liver resection compared to left colon primary tumors (5-year OS, 31.4% vs. 54.0% [P = 0.011]). Mutation frequencies were: 45.9% for RAS ; 2.4% for BRAF ; 8.4% for PIK3CA ; 0.2% for PTEN ; 0.4% for MET ; 12.1% for APC ; 24.3% for TP53. RAS (5-year OS, 40.8% vs. 55.7% [P = 0.001], PIK3CA (5-year OS, 31.1% vs. 50.5% [P = 0.027]), and TP53 mutation (5-year OS, 42.7% vs. 50.8% [P = 0.035]) were associated with worse OS after liver resection. On multivariable analyses, RAS (hazard rato [HR] 1.27; P = 0.033) and TP53 mutation (HR 1.35; P = 0.014) were significantly associated with poor OS after adjustment for covariates. Co-mutation in RAS/TP53 (12.4%) was associated with the worst oncologic outcome (HR 1.81; P<.001). Notably, while the negative prognostic impact of RAS mutation did not differ significantly according to primary tumor location, the adverse effect of TP53 mutation was limited to rectal cancer (interaction P = 0.002). In this study, MSI-high (2.3%) was not associated with survival. Conclusions: Both RAS and TP53 mutation are associated with worse survival following CRLM resection. In contrast to RAS mutation, the negative prognostic impact of TP53 mutation appears to be limited to CRLM from the rectal origin.