Background: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), acting via the Fn14 cell surface receptor, is a multifunctional pro-inflammatory/pro-angiogenic cytokine that participates in wound repair and tissue regeneration in different tissues. Studies have shown that TWEAK induces embryonic fibroblast proliferation through Ras/ERK signaling pathway. TWEAK produced in the tumor microenvironment acts on vascular endothelial cells and contributes to inflammatory angiogenesis in mCRC pts. In this study, we tested whether SNPs in TWEAK (rs3803800, rs1128963) and Fn14 (rs8052002, rs13209) predict clinical outcome in mCRC pts treated with first line FOLFIRI/BEV in two independent cohorts. Methods: Genomic DNA was isolated from blood or tissue samples of 525 pts treated with first-line FOLFIRI/BEV in FIRE-3 arm B (n = 295) and TRIBE arm A (n = 230) trials. FIRE-3 arm B served as the training set (Median follow up: 39.6 mos; Median PFS: 11.3 mos. and OS: 25 mos). TRIBE arm A served as the validation set (Median follow up: 45.1 mos; Median PFS and OS: 10.4 and 27.3 mos. PCR-based DNA sequencing was used to determine SNPs, which were selected based on frequency and function. FIRE-3 FOLFIRI/Cet (n = 297) was control arm. Results: In the overall population analysis, the TWEAK rs3803800 was significantly associated with shorter PFS (9.2 mos) compared to carrying the G/G genotype (11.3 mos) in the FIRE-3 trial in both univariate (HR: 1.39 [1.03-1.86]; P = 0.026) and multivariate analyses (HR: 1.50 [1.11-2.03], P  =  0.008). For KRAS mutant pts in the TRIBE trial, any A allele of TWEAK rs3803800 was associated with a similar trend toward worse PFS compared to G/G in multivariate analyses (HR: 1.64 [0.94-2.86], p  =  0.079), which is confirmed in the FIRE-3 trial (8 v. 12.3 mos, logrank test P = 0.019)(HR: 2.11 [0.97-4.49], Wald test P  =  0.058). No significant difference in control arm. Conclusions: This study provides the first evidence that TWEAKrs3803800 could be a predictive marker for PFS in mCRC pts treated with first line FOLFIRI/BEV. It also retained a significant correlation with outcomes related to KRAS mutation, which was confirmed in a validated cohort.