Background: RNA binding proteins (RBPs) post-transcriptionally regulate gene expression by stabilizing or destabilizing target messenger RNA. Although alteration of RBPs affects many steps of cancer development, its clinical implication in mCRC remains unclear. Methods: We analyzed data from mCRC patients (pts) enrolled in three first-line randomized trials (FIRE-3, TRIBE, and MAVERICC). Genomic DNA from blood samples of pts was genotyped through the OncoArray, a custom array manufactured by Illumina. Candidate 30 SNPs in 10 RBP genes (MSI1, MSI2, ELAVL1, RBM3, LIN28A, LIN28B, IGF2BP1, IGF2BP2, IGF2BP3, ZFP36) were tested on association with progression-free survival (PFS) and overall survival (OS). To evaluate prognostic effects and heterogeneities across treatment arms, meta-analysis approach using the METASOFT software was conducted. We also tested interaction between each SNP and treatment within each trial, i.e. FIRE-3 cohort (FOLFIRI+cetuximab (Cet) vs FOLFIRI+bevacizumab (Bev)) and MAVERICC cohort (FOLFIRI+Bev vs FOLFOX6+Bev). For multiple testing, p values were adjusted by the false discovery rate (FDR) method. Results: A total of 884 pts’ SNPs data were available (FIRE-3: n = 236, TRIBE: n = 324, and MAVERICC: n = 324). Meta-analysis combining three trials showed RBM3 rs926152 (adjusted p = 0.045) and RBM3 rs2249585 (adjusted p = 0.016) were significantly prognostic for PFS. Whereas, in terms of OS, only LIN28B rs314277 (adjusted p = 0.045) was significant, and RBM3 rs926152 (adjusted p = 0.057) and RBM3 rs2249585 (adjusted p = 0.059) had a trend. Interaction test showed several SNPs were potentially predictive (raw p< 0.05), although without any significance after FDR adjustment: in FIRE-3 cohort, MSI2 rs1822381, RBM3 rs926152, LIN28B rs221635, IGF2BP1 rs2969 for OS; in MAVERICC cohort, MSI1 rs1179442 and MSI2 rs3826301 for OS, ELAVL1 rs4804244 for PFS. Conclusions: Our results indicate prognostic potential of SNPs in RBP genes, such as RBM3 and LIN28B, in mCRC. However, we find no distinct evidence that these SNPs can predict differential effect between Cet and Bev, or between oxaliplatin- and irinotecan-based chemotherapy.