Abstract Background Irinotecan have been well known to correlate between UGT1A1 polymorphisms (UGT1A1) and adverse events. Modified XELIRI (irinotecan 200 mg/m2 on day 1, capecitabine 1600 mg/m2 on days 1 to14 every 3 weeks) has shown non inferiority of overall survival compared with FOLFIRI based on "Asian XELIRI ProjecT" (AXEPT) as second line chemotherapy for patients with mCRC. In this preplanned analysis of the AXEPT trial, we evaluated the relationship between UGT1A1 and the efficacy and safety of irinotecan-based chemotherapy. Methods Patients were randomized FOLFIRI ± bevacizumab (BV) or modified XELIRI ± BV based on UGT1A1 results (wild type, heterozygosity, and homozygosity). With regard to irinotecan dosage in both treatment arms, the reduced dosage (150mg/m2) were administered in case of homozygosity. Assessed endpoints were overall survival (OS), progression free survival (PFS), overall response rate (ORR), relative dose intensity (RDI) and safety. Result UGT1A1 was available for all 650 randomized patients (wild type, 309 (47.5%) heterozygosity, 291 (44.8%) and homozygosity, 50 (7.7%)). Median OS was of patients with a wild/hetero/homo was 14.3, 18.3 and 9.1 months in FOLFIRI arm and 18.1, 16.3 and 13.0 months in mXELIRI arm, respectively. Median PFS of patients with a wild/hetero/homo was 6.8, 8.8 and 4.8 months in FOLFIRI arm and was 8.3, 8.7 and 6.5 months in mXELIRI arm, respectively. Grade 3, 4 toxicities of special interests (wild/hetero/homo) were neutropenia (35.9%/50.4%/45.8% in FOLFIRI arm and 17.0%/15.7%/21.7% in mXELIRI arm), febrile neutropenia (5.9%/2.3%/4.2% in FOLFIRI arm and 1.4%/4.3%/8.7% in XELIRI arm), and diarrhea (1.3%/6.0%/0% in FOLFIRI arm and 4.8%/10.7%/0% in mXELIRI arm). Conclusions mXELIRI±BV was showed the good efficacy and well tolerated in patients with all UGT1A1 polymorphisms. mXELIRI+BV could be an alternative to FOLFIRI as a standard second line backbone treatment for mCRC.