UGT1A1*28/*6 as predictors of severe irinotecan-related diarrhea (SIRD) were duplicated by many studies. However, some patients of lower risk genotype (UGT1A1*1/*1) still suffered SIRD and the extremely low frequency of UGT1A1*6/*6 limited its clinical usage. Previous studies proved that the transforming growth factor (TGFB) family may have some effect on MTX-induced mucositis. However, the associations between TGFB gene variants and SIRD have never been reported so far. Our aim was to improve the predictive value of UGT1A1 gene variants on SIRD. Six SNPs (TGFB1 rs1800469; TGFBR1 rs10733710, rs334354 and rs6478974; TGFBR2 rs3087465; UGT1A1*6) and UGT1A1*28 were selected for genotyping in 160 metastatic colorectal cancer patients treated with irinotecan in a prospective multicenter trial (NCT01282658). UGT1A1*6, UGT1A1*28, rs1800469 and rs3087465 were all associated with SIRD (p = 0.026, 0.014, 0.047 and 0.045 respectively). A novel genetic score model (with a cut off value of 1.5) based on them was created to predict SIRD (OR = 11.718; 95 % CI 2.489-55.157, p = 0.002). In patients of gene score > 1.5, the risk of SIRD was much higher (23.5 vs. 2.8 %, p = 2.24E-04) and continued in the first 6 cycles of chemotherapy, while in patients with gene score a parts per thousand currency sign1.5, the risk was much lower and none of them suffered SIRD after the first cycle of chemotherapy (p = 0.0003). The novel genetic score model improved the predictive value of UGT1A1 on SIRD. If validated, it will provide valuable information for clinical use of irinotecan.