Objective To compare and evaluate the effectiveness and safety of irinotecan (IRI) versus oxaplatin (OXA), in combination with 5-FU/LV for patients with advanced colorectal cancer. Methods The literature search, study selection and assessment, data collection and analysis were undertaken by two reviewers according to the Cochrane Handbook for Systematic Reviews of Interventions. Randomised controlled trials (RCTs) or quasi-RCTs comparing IRI versus OXA, in combination with 5-FU/LV in the treatment of advanced colorectal cancer were collected. Results Seven studies involving 2107 patients were included. The OXA/5-FU/LV regimen was superior or at least equal to the IRI/5-FU/LV regimen in prolonging overall survival and time to progression. The OXA/5-FU/LV regimen showed a higher response rate and was associated with lower toxicities. Conclusion Compared with IRI, OXA is more appropriate for the treatment of advanced colorectal cancer when combined with 5-FU/LV.