Background: The MAPK-interacting kinase 1 (MKNK1) is localized downstream of the RAS/RAF/ERK and the MAP3K1/MKK/p38 signaling pathway. Through phosphorylation MKNK1 regulates the function of eukaryotic translation initiation factor 4E (eIF4E), a key player in translational control, whose expression is mostly upregulated in cancer patients. Preclinical data also suggest an influence of MKNK1 on angiogenesis and endothelial cell migration. We therefore hypothesize that variations in the MKNK1 gene may predict outcome in patients (pts) with metastatic colorectal cancer (mCRC) treated with first-line FOLFIRI and bevacizumab (bev). Methods: 295 pts with mCRC enrolled in the phase III FIRE-3 trial and treated with first-line FOLFIRI and bev were included in this study. Genomic DNA was extracted from formalin fixed paraffin embedded tissue. 6 functional SNPs in 6 genes (MKNK1, EIF4E, EIF4G, 4EBP1, hnRNPA1 and Spry2) 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; primary tumor site right/left = 74/215;median PFS/OS = 10.2/24.2 months. The MKNK1 rs8602 SNP showed significant association with progression-free survival (PFS). C allele carriers had a longer median PFS than those with an AA genotype (10.3 vs 7.7 months) in both univariate (HR 1.79, p = 0.009) and multivariate analysis (HR 1.80, p = 0.019). Additionally males and pts with left-sided cancers harboring any C allele had a better overall survival (OS) than those with an AA genotype (26.1 vs 18.2 months, HR 1.94, p = 0.025) and (28.1 vs 18.4 months, HR 2.28, p = 0.002) respectively. These associations remained significant in multivariate analysis (HR 1.94, p = 0.047 and HR 2.28, p = 0.008). Conclusions: Our results provide the first evidence that the MKNK1 SNP rs12218 might serve as a predictive marker in pts with mCRC treated with FOLFIRI and bev in the first line setting. Additionally MKNK1 rs12218 might also be prognostic depending on gender and tumor location. Targeting MKNK1 might be a promising approach to improve our treatment options against mCRC.