Objective: The aim of the study was to investigate the efficacy and safety of raltitrexed/bevacizumab in combination with irinotecan or oxaliplation for advanced colorectal cancer as the second-line and second-line above treatments. Methods: Fifteen cases of advanced colorectal cancer were enrolled to receive regimens including raltitrexed/bevacizumab combined with irinotecan or oxaliplation. Two cases were treated with raltitrexed + bavacizumab regimen, 9 cases with raltitrexed + bavacizumab + irinotecan regimen, and 4 cases with raltitrexed + bevacizumab + oxaliplation regimen. The doses of the drugs were as follows: bevacizumab 5 mg/kg ivgtt, d1; raltitrexed 2.0 mg/m2 ivgtt 15 min, d2; irinotecan 180 mg/m2 ivgtt 1 h, d2; and oxaliplatin 85 mg/m2 ivgtt 2 h, d2. Two weeks was a cycle for each regimen. Results: The efficacy of the 15 patients could be evaluated. Two cases were in PR,10 cases in SD, 3 cases in PD, the response rate was 13.3%, and the disease control rate was 80.0%. The median progress-free survival was 5.1 months(95% CI: 3.404–6.813 months), and the median overall survival was 11.5 months(95% CI: 8.985–13.930 months). The adverse effects included anorexia, nausea/vomiting, fatigue, leucopenia, thrombocytopenia, etc, and the main 3–4 grades adverse effects were anorexia, nausea/vomiting, fatigue, and thrombocytopenia. Conclusion: Raltitrexed/bevacizumab combined with irinotecan or oxaliplatin as the secondline and second-line above treatments for advanced colorectal cancer has high disease control rates, and the adverse effect is well tolerated. The combined regimen can be recommended as a phase III clinical research and second-line and secondlines above treatments for advanced colorectal cancer.