Background: DNA hypermethylation in CpG islands (CIMP) has been shown to promote CRC by silencing the expression of tumor suppressor genes. However, global DNA hypomethylation is now considered a common characteristic of CRC. A new family of genes (TET) has been shown to play a crucial role in actively demethylating the DNA. We explored whether genetic polymorphisms in the genes which promote DNA methylation and demethylation are associated with outcome in pts enrolled in TRIBE and FIRE-3 trials. Methods: Genomic DNA from blood samples was genotyped through the OncoArray, a custom array by Illumina including 530K SNP markers. 17 functional SNPs within 11 genes related to methylation (DNMT1/3A/3B, MDM2) and demethylation pathways (TET1/2/3, IDH1/2, MBD4, TDG) were analyzed. Results: A total of 451 pts were included. FOLFIRI/bevacizumab (bev) arms from TRIBE (N = 215, median PFS/OS: 9.7/26.3 months (mts)) and FIRE3 (N = 107, median PFS/OS: 11.6/31.5 mts) served as discovery and validation cohorts respectively. FIRE-3 FOLFIRI/cetuximab arm (N = 129, median OFS/OS: 12.8/49.8 mts) served as control. In the discovery cohort, overall pts carrying TET1 rs3814177 C/C variant showed lower response rate (RR) (42.1% vs 61.8%, p = 0.026) and shorter median PFS (9.5 vs 10.3 mts; HR = 1.54, 95%CI = 1.04-2.27; p = 0.024, univariate analysis) compare to those with any T allele. The effect was more significant among KRAS mutant pts in RR (21.4% vs 60.8%, p = 0.007) and median PFS (8.6 vs 9.5 mts) both in univariate (HR = 2.00, 95%CI = 1.07-3.73; p = 0.020) and multivariable analysis (HR = 2.01, 95%CI = 1.03-3.92 p = 0.041). These findings were validated in overall pts in FIRE-3 cohort in median OS both in univariate (23.7 vs 41.9 mts; HR = 2.08, 95%CI = 1.07-4.05; p = 0.023), and multivariable analysis (HR = 2.36, 95%CI = 1.15-4.81; p = 0.019). No significant association was observed in the control arm. Conclusions: Our results provide the first evidence that TET1 polymorphism may be used as a predictive biomarker in mCRC pts treated with FOLFIRI/bev. Therefore, TET enzymes could serve as promising new treatment targets for mCRC pts.