To explore the impact of KRAS, NRAS and BRAF mutations as well as KRAS mutation variants in patients with metastatic colorectal cancer (mCRC) receiving first-line therapy. A total of 1239 patients from five randomized trials (FIRE-1, FIRE-3, AIOKRK0207, AIOKRK0604, RO91) were included into the analysis. Outcome was evaluated by the Kaplan–Meier method, log-rank tests and Cox models. In 664 tumors, no mutation was detected, 462 tumors were diagnosed with KRAS-, 39 patients with NRAS- and 74 patients with BRAF-mutation. Mutations in KRAS were associated with inferior progression-free survival (PFS) and overall survival (OS) multivariate hazard ratio (HR) for PFS: 1.20 (1.02–1.42), P = 0.03; multivariate HR for OS: 1.41 (1.17–1.70), P < 0.001. BRAF mutation was also associated with inferior PFS multivariate HR: 2.19 (1.59–3.02), P < 0.001 and OS multivariate HR: 2.99 (2.10–4.25), P < 0.001. Among specific KRAS mutation variants, the KRAS G12C-variant (n = 28) correlated with inferior OS compared with unmutated tumors multivariate HR 2.26 (1.25–4.1), P = 0.001. A similar trend for OS was seen in the KRAS G13D-variant n = 71, multivariate HR 1.46 (0.96–2.22), P = 0.10. More frequent KRAS exon 2 variants like G12D n = 152, multivariate HR 1.17 (0.86–1.6), P = 0.81 and G12V n = 92, multivariate HR 1.27 (0.87–1.86), P = 0.57 did not have significant impact on OS. Mutations in KRAS and BRAF were associated with inferior PFS and OS of mCRC patients compared with patients with non-mutated tumors. KRAS exon 2 mutation variants were associated with heterogeneous outcome compared with unmutated tumors with KRAS G12C and G13D (trend) being associated with rather poor survival.