Background: TAMs with the M2-like phenotype are regulated by NF-kB pathway including TBK1, which can influence tumor progression by secretion of proangiogenic factors and tumor promoting cytokines, such as VEGF-A and CCL18. These factors drive tumor angiogenesis, migration and immunosuppression. The CCL2/CCR2 axis, histidine-rich glycoprotein (HRG), PIGF and VEGF play a critical role in the polarization of M1 and M2 phenotypes and the recruitment of TAMs to tumor microenvironment. We hypothesized that genes involved in regulating TAMs may predict outcome of bev-based therapy in patients (pts) with mCRC. Methods: We analyzed genomic DNA extracted from blood or tumor samples of pts receiving bev plus FOLFIRI in 2 prospective trials, using PCR-based direct sequencing. Eleven functional polymorphisms in 7 genes (CCL2, CCR2, HRG, PIGF, NFKB1, TBK1 and CCL18) were tested for associations with clinical outcome in a discovery cohort of 228 pts (male 61%, median age 60, follow-up time 27 months [m]) enrolled in TRIBE (T) trial (NCT00719797), then validated in 244 KRAS exon 2 (KRAS) wild-type (wt) pts (male 69%, median age 64, follow-up time 39 m) enrolled in FIRE3 (F) trial (NCT00433927). 246 pts receiving cetuximab plus FOLFIRI in F served as negative control. Results: TBK1 rs7486100 (A > T) was associated with response rate (RR) and overall survival (OS) in KRAS wt pts of T cohort (n= 95, any T vs A/A: 58 % vs 82 %, p= 0.046; 25.1 m vs 49.1 m, adjusted HR 2.39, p= 0.046, respectively). In F cohort, the association was observed for progression-free survival (any T vs A/A: 10.1 m vs 12.3 m, adjusted HR 1.42, p= 0.047) although there was no statistically association with RR and OS (23.7 m vs 28.6 m, p= 0.15). No polymorphism was established between KRAS mutant of T cohort and F cohort. No association was seen in control. Conclusions: TBK1 rs7486100 is associated with outcome of bev-based chemotherapy in mCRC pts, suggesting that NF-kB signaling may play a critical role in tumor angiogenesis as an independent pathway. Our results also suggest that TBK1 may be a potential biomarker to identify pts benefitting from bev-based treatment.