Background: CRC is generally characterized by aberrant Wnt signaling. Wnt signaling pathway genes AXIN2 and TCF7L2 complex control the proliferation and differentiation of intestinal epithelial cells. Previous study showed polymorphisms in TCF7L2 and AXIN2 were associated with increase risk of colon cancer. We tested the hypothesis whether single nucleotide polymorphisms (SNPs) in TCF7L2 (rs7903146) and AXIN2 (rs2240308, rs3923087) will predict clinical outcome in a cohort of mCRC pts treated with first line FOLFIRI/BEV. Methods: Genomic DNA were extracted from blood of 455 mCRC pts which prospectively enrolled in a pharmacogenetic translational study. Females(n=172) and males(n=252); Median follow up is 24 months, median PFS and OS were 10.5 and 29.9 months, respectively. Candidate SNPs were analyzed by PCR-based direct sequencing. Results: In the overall population analysis, TCF7L2 and AXIN2 polymorphisms were not associated with OS and PFS, but our data showed that 2 polymorphisms may predict clinical outcome when adjusted by pts gender and tumor location: 1) In right-sided tumors, male pts with any T allele of TCF7L2rs7903146 were associated with significantly worse PFS in comparison to those carrying C/C genotype (HR: 2.15; 95% CI: 1.09-4.22; P = 0.027, log-rank test). However, female pts with any T allele reversly showed better PFS compared with those carrying C/C variants (HR: 0.39; 95% CI: 0.17-0.94; P = 0.035, logrank test). 2) In women, pts with AXIN2 rs2240308 any A allele had better PFS and OS in right-sided tumors compared to those with any A allele but located in left side(p_interaction=0.047)(PFS) and (p_interaction=0.025)(OS), respectively. Conclusions: Our data show for the first time Wnt signaling pathway gene polymorphisms TCF7L2 rs7903146 and AXIN2 rs2240308 may predict PFS and OS in mCRC pts treated with first-line FOLFIRI/BEV. More importantly, this predictive value is dependent on gender and tumor location, suggesting a different role of Wnt signaling in female vs male and in right vs left side tumor. Our preliminary data warrants clinical trial validation.