Background: Reactive oxygen species activate RAS/MAPK signaling either through inactivation of phosphatases or by direct oxidation of kinases. We hypothesized that functional genetic variants in genes involved in the antioxidant system may be associated with the efficacy of cetuximab in mCRC patients. Methods: We analyzed genomic and clinical data from FIRE-3, a phase III trial which compared cetuximab and bevacizumab in combination with FOLFIRI in untreated mCRC patients. Genomic DNA extracted from blood samples was genotyped using an OncoArray (Illumina, Inc., San Diego, CA, USA). Candidate 13 functional single nucleotide polymorphisms (SNPs) (TXN rs2301242, TXN rs2301241, TXN2 rs4821494, TXN2 rs9619611, TXN2 rs59841625, CAT rs7943316, CAT rs564250, CAT rs11604331, CAT rs1001179, CAT rs769217, GPX4 rs757229, GPX4 rs4807542, and GPX4 rs713041) were tested for association with progression-free survival and overall survival (OS), using log-rank test and Cox proportional hazards model. To confirm the predictive value, the treatment-by-SNP interaction was tested. Results: A total of 236 patients were available for the SNP analyses (cetuximab arm, n = 129; bevacizumab arm, n = 107). In the cetuximab arm, two SNPs were significantly associated with clinical outcomes in univariate analyses: TXN2 rs4821494 (T/T vs any G allele, hazard ratio [HR] on OS = 2.17, 95% confidence interval [CI] = 1.04–4.56, log-rank p = 0.04) and GPX4 rs4807542 (G/G vs any A allele, HR on OS = 2.04, 95% CI = 1.05–3.98, log-rank p = 0.03). Multivariate analysis confirmed the significance in TXN2 rs4821494 (T/T vs any G allele, HR on OS = 2.47, 95% CI = 1.06–5.72, p = 0.03). In the bevacizumab arm, univariate analyses did not detect any significant associations between the SNPs and clinical outcomes. Treatment-by-SNP interaction test showed the significant predictive value of TXN2 rs4821494 in terms of OS (p = 0.03). Conclusions:TXN2 rs4821494 involved in the antioxidant system may predict the efficacy of cetuximab, in comparing with bevacizumab, in the first-line treatment of mCRC. Our novel findings warrant further validation studies.