Purpose: This systematic analysis was conducted to evaluate the efficacy and safety of pemetrexed based salvage chemotherapy for treatment of patients with metastatic colorectal cancer. Methods: Clinical studies evaluating the efficacy and safety of pemetrexed based regimens on response and safety for patients with colorectal cancer were identified using a predefined search strategy. Pooled response rates (RRs) were calculated. Results: For pemetrexed based regimens, 4 clinical studies including 201 patients with advanced colorectal cancer were considered eligible for inclusion. The analysis suggested that, in all patients, pooled RR was 20.4% (41/201). Major adverse effects were neutropenia, anorexia, fatigue, and anemia. No treatment related death occurred with pemetrexed based treatment. Conclusion: This systematic analysis suggests that pemetrexed based regimens are associated with mild activity with good tolerability in treating patients with metastatic colorectal cancer.