Background: Cetuximab(cet) is an anti-EGFR mAb which enhances the antibody-dependent cellular cytotoxicity (ADCC) by Natural Killer (NK) cells in EGFR+ CRCs. Overexpression of MHC class I antigen E (HLAE), and its membrane stabilizer, βeta-2 microglobulin (β2M) inhibit cet-induced ADCC. We hypothesize that single nucleotide polymorphisms (SNPs) in HLAE/β2M will influence cet-dependent NK cell lysis and clinical outcomes. Methods: Genome wide association studies were conducted on whole blood from 236 mCRC pts in the randomized phase III FIRE-3 trial treated with FOLFIRI/cet(n = 129) and FOLFIRI/bevacizumab(bev)(n = 107). The OncoArray database provided by Illumina containing 530K SNP markers from these pts was used to extract data on 4 functional SNPs from β2M and HLAE. Log-rank test and Cox proportional hazard regression models evaluated SNP associations with PFS/OS in uni- and multivariable analyses. Results: FOLFIRI/cet and FOLFIRI/bev cohort characteristics: median FU (29.1/26.7mo); PFS (12.8/11.5mo); OS (49.8/31.4mo); RAS WT(64%/62%) and RAS mut (15%/16%). Multivariable analysis showed worse PFS in RAS WT pts treated with FOLFIRI/cet with HLAErs1059510 T/T alleles (12.2 vs 13.3 mo; HR = 2.59; 95%CI = 1.05-6.39; p = 0.039) and HLAErs1264457 G/G alleles (12.3 vs 12.9 mo; HR = 2.36; 95%CI = 1.14-4.88; p = 0.021). These effects were not observed in RAS mut pts. β2Mrs1901531 mutant C allele carriers showed improved OS (67.4 vs 40.9 mo) independent of RAS status in FOLFIRI/cet arm in both univariate (HR = 0.27; 95%CI = 0.12-0.59; p < 0.001) and multivariable analysis (HR = 0.19; 95%CI = 0.07-0.48; p < 0.001). No significance was observed in FOLFIRI/bev overall or FOLFIRI/bev RAS WT pts. Conclusions: For the first time, we show that clinical outcomes in mCRC pts treated with FOLFIRI/cet are predicted by genetic variations in HLAE/β2M, which are not observed in FOLFIRI/bev. The predictive utility of HLAE is dependent on RAS status, whereas that of β2M is independent of RAS. The HLAE/β2M complex could be a promising therapeutic target for overcoming cet resistance. Validation in larger cohorts is required.