Background: An enterocyte subtype of the Colorectal Cancer (CRC) Assigner classifier has shown to confer benefit from oxaliplatin in adjuvant treatment for stage III CRC. MS4A12 belongs to the enterocyte subtype-specific gene, whose expression is regulated by endogenous CDX2. We tested whether single nucleotide polymorphisms (SNPs) in enterocyte-related genes predict oxaliplatin efficacy in first-line treatment for metastatic CRC (mCRC). Methods: Three different cohorts of mCRC patients (pts) (total 603) were included in this study: discovery cohort receiving FOLFOX ± bevacizumab (BV) (n = 146, median age = 61, median follow-up = 45.0 mos); validation cohort receiving FOLFOXIRI + BV (n = 230, TRIBE arm B, median age = 60, median follow-up = 46.5 mos); and control cohort receiving FOLFIRI + BV (n = 228, TRIBE arm A, median age = 60, median follow-up = 49.3 mos). SNPs were analyzed by PCR-based direct sequencing. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier curves, log-rank test, and Cox proportional hazards regression. Results: Among the SNPs tested in the discovery cohort, MS4A12 rs4939378 and CDX2 rs3812863 were extracted as potential markers of efficacy. In the validation cohort, any G allele in MS4A12 rs4939378 was associated with longer PFS than the A/A variant in univariate analysis (12.4 vs. 10.9 mos, HR 0.70, 95%CI: 0.49-0.99, P= 0.033) and multivariable analysis (HR 0.65, 95%CI: 0.44-0.97, P= 0.035). The findings were more evident in the KRAS mutant than KRAS wild-type pts. In contrast, KRAS wild-type mCRC pts with the G/G variant in CDX2 rs3812863 had a longer PFS than those with any A allele (32.3 vs. 10.3 mos, HR 0.39, 95%CI: 0.19-0.81, P= 0.004), and the trend remained in multivariable analysis though without statistical significance (HR 0.48, 95%CI: 0.21-1.09, P= 0.08). These findings were not confirmed in the control cohort. Conclusions: The enterocyte subtype might affect the antitumor activity of oxaliplatin in not only early stage but also metastatic disease in CRC. Genetic variants in MS4A12 and CDX2 gene polymorphisms may serve as potential predictive marker of oxaliplatin-based treatment in mCRC pts.