Next-generation sequencing (NGS) provides a molecular rationale to inform prognostic stratification and to guide personalized treatment in cancer patients. Here, we determined the prognostic and predictive value of actionable mutated genes in metastatic colorectal cancer (mCRC). Among a total of 294 mCRC tumors examined by targeted NGS, 200 of them derived from patients treated with first-line chemotherapy plus/minus monoclonal antibodies were included in prognostic analyses. Discriminative performance was assessed by time-dependent estimates of the area under the curve (AUC). The most recurrently mutated genes were (64%), or (49%), (15%), (14%), (13%), and (9.5%). Mutations in correlated with worse OS rates ( = 0.036; HR, 2.24) independently of clinical factors. Concurrent mutations in and were associated with increased risk of death ( = 0.02; HR, 3.31) as well as double-mutated and ( = 0.03; HR, 2.91). Analysis of the MSK-IMPACT mCRC cohort (N = 1095 patients) confirmed the same prognostic trend for the previously identified mutated genes. Addition of the mutational status of these genes upon clinical factors resulted in a time-dependent AUC of 87%. Gene set enrichment analysis revealed specific molecular pathways associated with and mutations in -defficient tumors. Conclusively, and mutations in -altered tumors were predictive of a negative prognostic outcome in mCRC patients treated with first-line regimens.