Background: Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase with functions that counter-balance kinase-mediated phosphorylation throughout cell signaling networks. PP2A was reported to upregulate the angiogenesis, while negatively regulate the pathways downstream of receptor tyrosine kinases at multiple nodes. Previous studies showed PP2A variants were associated with the increased risk of cancer. Therefore, we hypothesized that PP2A variants may predict first-line treatment outcome in mCRC pts treated with bevacizumab (bev)/cetuximab (cet)-based chemotherapy. Methods: Genomic DNA from blood samples of pts enrolled in two independent randomized trials, TRIBE (bev arm, n=215, as discovery cohort) and FIRE-3 (bev arm, n=107, as validation cohort; cet arm, n=129, as control cohort), was genotyped through the OncoArray, a customized array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of 17 selected SNPs in 3 main PP2A core subunits (PPP2CA, PPP2R1B, PPP2R1A), one phosphatase activator (PPP2R4) and 2 endogenous inhibitors (TIPRL, CIP2A) was analyzed. Results: In the discovery cohort, pts with PPP2R4 rs2541164 A/A (N=16) showed significantly shorter overall survival (15.3 vs 27.3 months) compared to carriers of any G allele (N=198) in both univariate (hazard ratio [HR]=1.8; 95% confidence interval [CI]: 1.1-3.1; p=0.02) and multivariate (HR=2.4; 95%CI: 1.4-4.4; p=0.006) analysis. These data were validated in the FIRE-3 bev cohort in both univariate (A/A vs. Any G: 17.3 vs 39.9 months, HR=2.8, 95%CI: 1.4-5.9, p=0.004) and multivariate (HR=4.3, 95%CI: 1.5-12.2, p=0.0095) analysis. Conversely, pts carrying CIP2A rs13069780 C/C (N=24) only showed significantly longer progression-free survival (17.7 vs 12.3 months) than carriers of any T allele (n=105) in the FIRE-3 cet cohort in both univariate (HR=0.6; 95%CI 0.4-0.99; p=0.04) and multivariate (HR=0.5; 95%CI 0.3-0.94; p=0.02) analysis, but no association were observed in the bev cohort of TRIBE and FIRE-3. Conclusions: Our study demonstrated for the first time that PPP2R4 polymorphisms could predict outcomes of bev-based treatment in mCRC patients; Meanwhile CIP2A polymorphism could predict outcomes of cet-based treatment in mCRC patients. These findings support a possible role of the PP2A variants in contributing to resistance to anti-VEGF/EGFR treatment.