Background: Components of the coagulation cascade and surface proteins of platelets are involved in the regulation of angiogenesis. There are preliminary data suggesting that antithrombin III (ATIII), beside its anti-angiogenic effects, might also inhibit cancer cell migration and invasion. We therefore hypothesize that genes encoding regulatory proteins within the coagulation cascade and surface proteins of platelets may predict outcome in patients with metastatic colorectal cancer (mCRC). Methods: 295patients with mCRC enrolled in the randomized phase III FIRE-3 trial and treated with FOLFIRI and bevacizumab were included in this study. Genomic DNA was extracted from formalin fixed paraffin embedded tissue. 6 functional SNPs in 6 genes (FGB, F2, F2R, SERPINC1, ITGA2B, ITGB3) were analyzed by PCR-based direct sequencing. Candidate SNPs and their correlation with outcome were analyzed by uni- and multivariate analysis. Results: Baseline characteristics were as follows: female/male = 99/196; median age = 65y (31-76) and median PFS/OS = 10.1/24.2 months. The SERPINC1 variant rs5877 encoding ATIII and the FGB SNP rs4220 encoding fibrinogen showed significant association with overall survival (OS). Patients with a C/C genotype of the SERPINC1 SNP rs5877 had a significantly worse OS than those harboring any T alleles (17.6 vs 25 months) in both univariate (HR 1.66, 95% CI 1.11-2.48, p = 0.011) and multivariate analysis (HR 1.74, 95% CI 1.15-2.64, p = 0.009). Similarly, A/A genotype carriers of the FGB SNP rs4220 showed a shorter OS compared to those with any G alleles (14.7 vs 24.8 months) in univariate (HR 1.90, 95% CI 1.05-3.42, p = 0.028) and multivariate analysis (HR 2.83, 95% CI 1.49-5.40, p = 0.002). Conclusions: This is the first report demonstrating that the SERPINC1 polymorphism rs5877 and the FGB SNP rs4220 might serve as predictive/prognostic biomarkers in patients with mCRC treated with FOLFIRI and bevacizumab in the first line setting.