Background: Cetuximab (CTX) and Panitumumab (PMB) therapies directed at EGFR have been restricted to left-sided CRC harboring wild-type KRAS (KRAS^WT), limiting their utility. Approximately 50% of mCRC fail to respond to EGFRi, thus identification of predictive biomarkers is an unmet need. Here we evaluate a CTX sensitivity score (CTX-S) that we previously reported (Yang M. et al., 2019), in a large, real-world population of RAS/BRAF mutant vs wild-type and in right- vs left-sided tumors. Methods: CTX/PMB-treated CRC specimens (n=1124) with clinical outcomes, NextGen Sequencing of DNA (592-gene panel or whole exome sequencing) and RNA (whole transcriptome sequencing) were tested at Caris Life Sciences (Phoenix, AZ). 1097 specimens were MSS as determined by IHC of MMR proteins and/or NGS. Association of CTX-S with RAS/BRAF mutation and tumor sidedness was performed in MSS tumors. Tumors with likely pathogenic mutations in KRAS, NRAS or BRAF were considered as RAS^MUT/BRAF^MUT, or RAS^WT/BRAF^WT if no mutation was detected for each gene. Samples were stratified based on CTX-S quintiles. Survival on EGFRi was calculated from the initiation of EGFRi to last contact using Kaplan-Meir method. Results: Higher CTX-S quintiles were significantly associated with longer survival on EGFRi in RAS/BRAF wild-type as well as -mutant subpopulations. Similar results were seen in left- vs. right-sided tumors (Table). Higher CTX-S quintiles were associated with a survival benefit in all CMS classes but CMS2; however, the vast majority of CMS2 tumors (460/467) were among the top 3 CTX-S quintiles. As the median survival among the top 3 quintiles was ~2-fold higher than the bottom 2 quintiles, we used stratification by the 40^th percentile for the genomic analysis. CTX-S >40^th percentile was associated with an increased prevalence in APC (91 vs 47%) and TP53 (93 vs 76%) mutations and decreased prevalence in BRAF (6 vs 32%), SMAD4 (8 vs 19%), RNF43 (1 vs 12%) and ATM (2 vs 5%) mutations (all q<0.05). Conclusions: Our data suggest that CTX-S may predict longer survival on EGFRi, surprisingly independent of RAS/BRAF mutation status as well as tumor sidedness. Patients with high CTX-S had increased prevalence of CMS2 and harbored more APC and TP53 mutations. A strong EGFRi biomarker would likely expand the utility of EGFRi to right-sided tumors and possibly to RAS^MUT tumors. Further validation of these biomarkers in a prospective clinical trial is warranted and could change our current standard of care for CRC.