PURPOSE: Human epidermal growth factor receptor 2 (HER2) amplification/overexpression (HER2-pos) is detected in 5% of RAS/BRAF wild-type metastatic colorectal cancers (mCRCs). Its prognostic/predictive role in terms of benefit from anti-EGFR/bevacizumab (bev) is debated. Similarly, the role of activating HER2 mutations (mut) is unclear. METHODS: We collected individual data of 1,604 patients with proficient mismatch repair (pMMR)/microsatellite stable (MSS) RAS/BRAF wild-type untreated mCRC with HER2 amplification/expression status available enrolled in eight randomized clinical trials (RCT; TRIBE2, TRIPLETE, VALENTINO, ATEZOTRIBE, PANDA, PANAMA, PARADIGM, and CALGB/SWOG80405). Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were assessed with respect to HER2 amplification/expression and HER2 mutational status and according to biologics (anti-EGFR/bev). RESULTS: Patients with HER2-pos were 81 (5%). HER2-pos patients experienced shorter PFS (median PFS [mPFS]: 9.8 v 12.2 months, hazard ratio [HR], 1.31, P = .02) and OS (median OS [mOS]: 28.0 v 34.9 months, HR, 1.37, P = .01), also after adjustment for covariates (PadjPFS = .02, PadjOS = .048). ORR was similar between HER2-pos and HER2-negative (HER2-neg) tumors (75% v 72%, odds ratio [OR], 1.21, P = .47). We found no interaction between HER2 amplification/expression status and biologics' effect in terms of PFS (Pint = .76), OS (Pint = .76), and ORR (Pint = .64). In left-sided HER2-pos tumors, outcomes were similar with chemotherapy plus bev/anti-EGFRs in terms of PFS (9.8 v 9.3 months, HR, 0.73, P = .29), OS (29.8 v 28.0 months, HR, 1.29, P = .40), and ORR (59% v 79%, OR, 0.39, P = .10). HER2-mutant tumors (2% of patients with HER2-neg tumors) showed shorter OS than HER2 wild-type ones (mOS: 23.7 v 34.4 months, HR, 1.56, P = .04) with no differential effect of biologics (PintORR = .81; PintPFS = .95; PintOS = .92). CONCLUSION: To our knowledge, this is the largest analysis of HER2 status in patients with untreated mCRC enrolled in RCT. Waiting for targeted approaches, HER2-pos and mut do not predict benefit from bev/anti-EGFRs and should be regarded as negative prognostic factors in pMMR/MSS RAS/BRAF wild-type mCRC.