Background: The secreted Wnt agonists of the R-spondin (RSPO) family, RSPO1-4, play important roles as Wnt coactivators by interacting with LGR receptors, leading to stabilization of Frizzles at the cell surface and resulting in various Wnt-related cellular and biological processes, including tumorigenesis. The novel Rspo-Wnt-VegfC-Vegfr3 pathway has been reported as bypass angiogenic pathway during tumor angiogenesis. Also, genomic alterations of RSPO genes were found in CRC. Therefore, we tested whether polymorphisms (SNPs) in RSPO1 (rs4074961, rs1134025), RSPO2 (rs601558, rs555008) and RSPO3 (rs1892172, rs10457487) could predict clinical outcome in mCRC pts treated with first line FOLFIRI/BEV enrolled in FIRE3 trial. Methods: Genomic DNA was isolated from tissue samples of 295 pts treated with first-line FOLFIRI/BEV in FIRE-3 trial. Median follow up: 39.6 mos; Median PFS: 11.3 mos. and Median OS: 25 mos. PCR-based DNA sequencing was used to determine SNPs. Results: Our data showed that RSPOs snps predict clinical outcome by pts tumor location and KRAS status. In left-side tumor pts, the RSPO2 rs555008 T/T genotype was significantly associated with shorter OS [23.7 (18.4-27.5) mos] compared to any G allele [31.9 (25-40) mos] in both univariate (P = 0.011) and multivariate analyses (P  =  0.05). The RSPO3 rs10457487 any C [11.7 (10.1-13) mos] was associated with longer PFS compared to A/A [9.1 (7.5-10.1) mos] in both univariate (P = 0.009) and multivariate analyses (P  =  0.024). For KRAS wild type pts, the RSPO2 rs555008 T/T was significantly associated with shorter OS [22.3 (17.5-26.4) mos] compared to any G allele [28.4 (22.7-35) mos] in univariate (P = 0.011). The RSPO3rs10457487 any C allele was significantly associated with longer PFS [10.8 (9.7-12) mos] compared to A/A [9.1 (7.6-10.1) mos] in univariate (P = 0.025) and had a similar trend in multivariate analyse (P  =  0.08). Conclusions: This study provides the first evidence that RSPO2 rs555008 and RSPO3 rs10457487 could be prognostic markers for OS and PFS in mCRC pts treated with first line FOLFIRI/BEV. The significant correlation with outcomes was dependent on tumor location and KRAS status.