Objective The gastrointestinal side effects and bone marrow suppression are main dose dependent toxicity of irinotecan, especially the unpredictable severe diarrhea. This study aimed to assess the clinical effect of octreotide combined with alanyl-glutamine on the prevention of irinotecan-caused tardive diarrhea in patients with colorectal cancer. Methods Sixty patients with advanced colorectal cancer who were scheduled irinotecan-based -chemotherapy were recruited and divided into prevention group (n=30) and control group (n=30). Patients in prevention group received octreotide 0.1mg tid via hypodermic injection and alanyl-glutamine10g qd ivgtt from the onset of chemotherapy to day 6. The incidence and severity of tardive diarrhea in both groups were compared. The large doses of loperamide amine were used to treat when patients with sparse stool or the increase in time. The montmorillonite powder, Bifidobacterium capsule and rehydration therapy were given when necessary. Results There were 12 cases with tardive diarrhea in control group with the incidence of 40%, including 6 cases (20%) of grade 2 diarrhea, 4 cases (13.3%) of grade 3 diarrhea, and 2 cases (6.7%) of grade 4 diarrhea. 4 cases occurred tardive diarrhea in prevention group with the incidence of 13.3% (P<0.05), and all of them were grade 2 diarrhea, and no grade 3~4 diarrhea occurred. Conclusions There were good preventive effect of octreotide combined with alanyl-glutamineon irinotecan-caused tardive diarrhea, which could improve the safety.