The purpose of this study is to evaluate the influence of germline polymorphisms of cytochrome P450 (CYP450) on objective response, progression-free survival (PFS) and overall suruvival (OS) in metastatic colorectal cancer (mCRC) receiving the combination chemotherapy of irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI). All SNPs in CYP450, whose minor allele frequency were more than 10 %, were genotyped in 82 patients with mCRC who received first-line FOLFIRI regimen. chi (2) test or Fisher's exact test was used to assess the correlation between SNPs and objective response as appropriate and log-rank test between SNPs and PFS or OS. Cox proportional hazards models were used to analyze the association of CYP450 gene polymorphisms and clinical factors for PFS and OS. No SNP showed predictive or prognostic value for clinical outcomes, except for CYP3A5 rs776746 A > G, which was significantly associated with PFS (P = 0.0002). Multivariate analysis confirmed its prognostic value for PFS (P = 0.002). CYP3A5 rs776746 A > G polymorphisms have a prognostic contribution toward FOLFIRI regimen in mCRC. This could represent a further step toward personalized therapy.