Whether UGT1A1*28 genotype is associated with clinical outcomes of irinotecan (IRI)-based chemotherapy in Colorectal cancer (CRC) is an important gap in existing knowledge to inform clinical utility. Published data on the association between UGT1A1*28 gene polymorphisms and clinical outcomes of IRI-based chemotherapy in CRC were inconsistent.Literature retrieval, trials selection and assessment, data collection, and statistical analysis were performed according to the PRISMA guidelines. Primary outcomes included therapeutic response (TR), progression-free survival (PFS) and overall survival (OS). We calculated odds ratios (OR) and hazard ratios (HR) with 95% confidence intervals (CI). Twelve clinical trials were included. No statistical heterogeneity was detected in analyses of all studies and for each subgroup. Differences in TR, PFS and OS for any genotype comparison, UGT1A1*28/*28 versus (vs) UGT1A1*1/*1 (homozygous model), UGT1A1*1/*28 vs UGT1A1*1/*1 (heterozygous model), and UGT1A1*28/*28 vs all others (recessive model, only for TR) were not statistically significant. IRI dose also did not impact upon TR and PFS differences between UGT1A1 genotype groups. A statistically significant increase in the hazard of death was found in Low IRI subgroup of the homozygous model (HR = 1.48, 95% CI = 1.06-2.07; P = 0.02). The UGT1A1*28 allele was associated with a trend of increase in the hazard of death in two models (homozygous model: HR = 1.22, 95% CI = 0.99-1.51; heterozygous model: HR = 1.13, 95% CI = 0.96-1.32). These latter findings were driven primarily by one single large study (Shulman et al. 2011).UGT1A1*28 polymorphism cannot be considered as a reliable predictor of TR and PFS in CRC patients treated with IRI-based chemotherapy. The OS relationship with UGT1A1*28 in the patients with lower-dose IRI chemotherapy requires further validation.