Background: FIRE-3 compared 1^st-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wt mCRC patients (pts). Methods: Tumor DNA was profiled by next-generation sequencing to explore molecular markers of prognosis. The biomarker evaluable subpopulation (n = 373) was representative of the ITT population. Treatment efficacy was determined in the quadruple wild-type (wt) population (RAS, BRAF, AKT, PI3K = “MAPK/mTOR wt”). Kaplan-Meier estimation and log-rank tests were employed for overall survival (OS). Hazard ratios (HR) were estimated using the Cox proportional hazard method. P-values were not adjusted for multiple testing Results: Overall frequencies were (%,n): MSI-h 2.7% (10); BRAFmut 12.1% (45); RASmut 32.7% (122); quadruple wt: 47.7% (178); TMB > 8: 15% (56). RAS, BRAF, MSI-h and quadruple-wt status were prognostic. Pts with low-frequent RAS mutations (RASmut < 5%) had a significantly longer OS when compared to pts with higher RAS mutational frequency. Conclusions: NGS analysis revealed distinct subgroups of mCRCs with different prognosis. MSI status had prognostic impact, but TMB could not be validated as a prognostic or predictive marker.