Objective To observe the clinical efficacy of irinotecan combined with capecitabine or tegafur-gimeracil-oteracil potassium in the second-line treatment of advanced colorectal cancer. Methods The clinical data of 19 patients with advanced colorectal cancer who were admitted to the Cancer Hospital of Chinese Academy of Medical Sciences and Peking Union Medical College from October 2014 to December 2017 were retrospectively analyzed, and these patients failed the first-line chemotherapy regimen. All patients were treated with irinotecan plus capecitabine or tegafur-gimeracil-oteracil potassium. The patient's short-term efficacy, adverse reactions, progression-free survival, and overall survival were analyzed. Results After treatment, the efficacy in 18 of the 19 patients with advanced colorectal cancer was evaluable, including partial remission in 3 patients, stable disease in 13 patients, and disease progression in 2 patients. The objective remission rate was 16.7％ (3/18), the disease control rate was 88.9％ (16/18), the median progression-free survival time was 7.6 months, and the median overall survival time was 23.3 months. All of the patients were well tolerated , and the grade 4 adverse reaction was presented as grade 4 neutropenia (1 case), grade 3 leukopenia (2 cases) and thrombocytopenia (1 case), grade 2 diarrhea (1 case), and grade 1 diarrhea (3 cases), and grade 1-2 liver injury (3 cases) and nephrotoxicity (2 cases). Conclusion Irinotecan combined with capecitabine or tegafur-gimeracil-oteracil potassium in the treatment of advanced colorectal cancer is effective and safe, which is worthy of clinical promotion.