Background: The aim of our study was to analyze the possible relationships between treatment efficacy, and germinal gene polymorphisms linked to the irinotecan in combination with bevasizumab or panitumumab and capecitabine or 5-FU that has been routinely used in our practice, in the management of metastatic colorectal cancer (CRC). Materials and Methods: Ninety-four Greek with histologically proven metastatic CRC were included in the study. Treatment was administered until disease progression or unacceptable toxicity, for a maximum of eight cycles. Patients were stratified into stable disease. (SD) and progressive disease. (PD). Associations between clinical data, KRAS, UGT1A1. (UGT1A1*28) and DPD (IVS14+1 G. > A) polymorphisms, and toxicity were analyzed. Results: Fifty-eight (61.70%) patients were characterized with SD disease and 36 (38.30%) with PD. There were not statistical significant differences between carriers of KRAS mutated alleles between SD and PD groups. No significant difference was found between response rates and toxicity and DPD or UGT1A1 genotypes. Our results suggested that determination of DPD or UGT1A1 genotypes could not be useful for predicting severe toxicity of irinotecan in our population. Conclusions: The clinical significance of the findings requires replication in larger populations. Furthermore, as 5.FU and irinotecan metabolism is complex, numerous genes in addition to DPD and UGT1A1 should be investigated.