Background: Anti-bodies targeting the epidermal growth factor receptor (EGFR) have shown efficacy in metastatic colorectal cancer (mCRC). The extended RAS analysis has further defined EGFR dependent tumors that are more sensitive to EGFR inhibition. Beyond RAS mutations, expression of EGFR ligands (amphiregulin (AREG) and epiregulin (EREG)) have shown predictive values. The challenge to move these biomarkers into clinic are the standardization of quantitative intra-tumor measurements. If germline single nucleotide polymorphisms (SNPs) in AREG and/or EREG would be predictive this could easily used in clinical practice. We have previously shown that rs1615111 associated with time-to-recurrence in gastric cancer. Aim of this study was to test the predictive value of rs1615111 in cetuximab treated mCRC patients. Methods: Genomic DNA was isolated from tissue samples of 299 patients (median age 64 years, male 67.2%) treated in first-line with either FOLFIRI cetuximab (n=139) or FOLFIRI bevacizumab (n=160) from the FIRE-3 trial (NCT00433927). In 174 samples, tumor cells were micro-dissected for mRNA extraction. rtPCR was carried out using LightCycler technology. All patients were KRAS/NRAS wild-type. The bevacizumab arm served as negative control arm. Results: The minor allele A of rs1615111 was associated with decreased tumor response (37% vs. 78.4%, two-sided Fisher’s p=0.02) shorter progression free survival (5.9 months vs. 10.6 months, logrank p=0.001 HR 3.46) and OS (11.4 months vs. 33.1 months, logrank p=0.001, HR 3.87) in FOLFIRI plus cetuximab treated patients. Low AREG mRNA expression was associated with short OS (3.2 months vs. 33.1 months logrank p<0.001, HR 0.08) but no association with rs1615111 could be established. In FOLFIRI plus bevacizumab treated patients rs1615111 did not have any predictive value. Conclusions: AREG SNP rs1615111 is predictive for cetuximab treatment. No prognostic value could be established. Biological function of rs1615111 remains unknown as it was not associated with mRNA expression. Beyond RAS mutations and EGFR ligand expression SNPs in AREG are new promising predictive marker for EGFR inhibitors. Prospective studies to validate and confirm these data are warranted.